Here’s Hippocrates, father of Western medicine: “It is very injurious to health to take in more food than the constitution will bear, when, at the same time one uses no exercise to carry off this excess.”

And here’s the blunt advice of Polybus, student (and son-in-law) of Hippocrates: “Persons of a gross relaxed habit of body, the flabby, and red-haired, ought always to use a drying diet . . . Such as are fat, and desire to be lean, should use exercise fasting; should drink small liquors a little warm; should eat only once a day, and no more than will just satisfy their hunger.”

Public health experts no longer disparage red-haired folks, and as far as I know, they don’t recommend drinking warmed-up liquors. But they’re still spreading the message of the harms of obesity, via television, magazines, school curricula, and even First-Lady policy agendas. These efforts have some merit. People who are obese (defined as having a BMI of 30 or higher) have an increased risk of developing heart disease, diabetes and some cancers compared with people who are not obese. And people who are severely obese have a higher death rate than thin people.

The message that thinner = better just seems intuitive, doesn’t it? I’ve certainly heard it all my life (or at least since 3rd grade, when I was mortified to be one of the chubby kids in gym class to not get the President’s Physical Fitness Award badge) and have never questioned it. But over the past few months, while researching a story published in today’s Nature, I’ve started to wonder whether we’ve gone too far in our cultural war against fat.

Weight is just one factor of many — sleep, diet, fitness, psychological health, socioeconomic status — that influence whether we are healthy or sick. But politicians don’t talk about a sleep deprivation epidemic; there is no Biggest Loser of Poverty reality TV show.

What’s more, the health risks of being “overweight” (defined as a BMI between 25 and 30) are not at all clear. As I describe in depth in the new story, mortality rates of people in the overweight category are actually 6 percent lower than those in the “normal” category, and some people who are overweight (and even mildly obese) show no signs of illness. Conversely, lots of thin people out there have heart disease and diabetes.

Yes, being obese usually takes a toll on health, no question. But guess how many obesity drugs or diet-and-exercise regimes have been proven to last more than a year or two?

Oh, right, zero.

And yet, the battle cry remains: if you’re obese, just crank up that willpower! Eat less, move more!

“I would like to believe that modern medicine and modern science can be better than just repeating a 2,000-year-old recommendation,” says Jeffrey Friedman, a molecular biologist and trained medical doctor at the Rockefeller Institute in New York. Friedman has many strong opinions about the so-called obesity “epidemic,” which we talked about at length over coffee recently.

Friedman has been studying the genetic roots of obesity for more than 30 years. In 1994 he made headlines for the discovery of leptin, a hormone that circulates in blood and turns off hunger signals in the brain. Subsequent studies have found genetic mutations in the leptin gene that cause rare cases of obesity. Twin studies have also shown that obesity has strong genetic roots (it’s about as heritable as height, in fact, and yet we don’t think of being too short or too tall as some kind of moral failing).

Despite these unquestionable genetic contributions, most of us think of weight as environmentally driven: a direct consequence of a person’s personal eating habits. It’s this emphasis on behavior that “gives the public a license to stigmatize the obese,” Friedman says.

“A lot of people try to couch it in ways that don’t as directly lead to stigmatization, but they end up always getting there,” Friedman says. “Because you end up saying, at some level, that the obese have made a series of poor choices that have led them to this.”

Friedman sees things quite differently, as he eloquently explained in a 2003 commentary in Science. Each of us, he argues, has a different genetic predisposition to obesity, shaped over thousands of years of evolution by a changing and unpredictable food supply. In modern times, most people don’t have to deal with that nutritional uncertainty; we have access to as much food as we want and we take advantage of it. In this context, some individuals’ genetic make-up causes them to put on weight — perhaps because of a leptin insensitivity, say, or some other biological mechanism.

In other words, morbidly obese people lost the genetic lottery. “The irony is, it’s the people who are the most obese who are stigmatized the most, and in fact, they’re the people who can do the least about it,” Friedman says.

Environment is important, of course: No one, no matter what their genome looks like, can become obese without food. But scientists don’t know most of the details of how the environment interacts with genes to control our eating habits. They don’t know why this system has such extreme variability in the human population. They don’t know why a (very select) few obese people can lose 50 percent of their weight and maintain that loss for decades. And, as I found in my story, researchers definitely don’t know why extra weight leads to sickness in some people but not in others. (It’s not even clear that fat tissue itself is harmful; it could just be an innocuous byproduct of a harmful diet, say, or of not exercising enough.)

This whole subject is steeped in political controversy and a wide array of financial interests, which has made it difficult for me to write about and to think about. But I’ve tried to be provocative in this post. Considering the economic and cultural investment we’ve put into the war on obesity, doesn’t the public deserve more transparent and rigorous discussions about it?

Is this a public health emergency that warrants the $1+ billion a year the U.S. is spending on it? Or are we fighting a war that’s unjustified, unjust, and impossible to win?

*

Quotes from Hippocrates and Polybus cited in this 2007 commentary by D. Haslam (.pdf here)

The cops round up the prostitutes, usually about a dozen of them, and bring them to an area set up with food, clothes, STD testing, and legal counsel. “They walk them over and say, ‘You would be going to jail if it was Tuesday. But it’s your lucky Wednesday’,” says Sara Katsanis, an associate in research at Duke University’s Institute for Genome Sciences and Policy. The police give them two options: either go to jail, or start a 14-day rehabilitation program known as the Prostitute Diversion Initiative, or PDI. So far hundreds of prostitutes have chosen the latter.

Since PDI launched in April of 2007, it has helped many prostitutes (almost all women) find addiction counseling, housing, and lawful employment. But many girls stay in the sex industry. It’s a dangerous profession, with a death rate six times higher than average (and a homicide death rate 18 times higher).

PDI participants may voluntarily submit a saliva sample for future DNA testing. The police will test the sample only if it’s relevant to some future crime — most likely, for a post-mortem identification. In other words, the only way the prostitute’s DNA donation can help her is if she turns up dead.

“Prostitutes are quite often, in Texas, victims of homicide, and quite often they don’t carry ID. So the police end up with a crime scene, a victim, and the inability to connect the dots,” Katsanis says. But there may be other beneficial uses for those saliva samples, she says.

Some of the Texas prostitutes, for example, may have been sold into the sex trade as children. Imagine a world in which secure, international databases could match genetic profiles of missing children or human trafficking victims — prostitutes, illegally adopted children, even child soldiers — with profiles submitted by their family members. As Katsanis writes in a commentary published today in Trends in Genetics, this kind of thing is already happening, but on a very small scale. In order for it to be really useful, she says, researchers, policy makers, law enforcement, and non-profits from many different countries will have to work out a whole lot of ethical, legal and logistical issues.

You’ve probably heard of the police using DNA databases to identify criminals — the Supreme Court is now deciding a case about this very thing, and Justice Samuel Alito said it might be “the most important criminal procedure case that this court has heard in decades.” But you might be surprised (I was) to learn that U.S. federal authorities also routinely use DNA information for immigration cases. When people want to enter the U.S. as refugees, they may submit DNA samples to prove they’re related to American citizens (a requirement for many refugees). Unlike the criminal DNA databases that are controlled by the government, for immigration cases the feds hire commercial laboratories to perform the tests and store the samples.

Indefinite storage of DNA, especially by the government, naturally raises concerns about privacy and trust. That’s doubly true for vulnerable populations, like children, immigrants and trafficking victims, who may not understand the language of consent forms or the purpose of the tests, or may feel coerced to consent. That makes the situation extremely challenging, but not impossible.

Boys rescued in Mexico after being trafficked as prostitutes. Photo by Jodi Cobb.

In 2004, José Lorente, a geneticist at the University of Grenada, started a foundation called DNA-Prokids with the mission of building DNA databases that would help find missing children. The organization has since sent thousands of free DNA testing kits to authorities in 16 countries, preventing (according to the New York Times) 200 illegal adoptions and reuniting 550 children with their families. For example, Brenda Corado, a Guatemalan, found her daughter Angela thanks to DNA testing. As the Times reported:

Ms. Corado had been walking on the street with Angela, then 21 days old, when two men got out of a car, snatched the baby from her arms and beat her until she passed out. What the men intended to do with the child is unclear. But Dr. Lorente believes that they probably intended to make money putting the child up for adoption.

Two months later, however, an infant girl was abandoned at a Christian television station in Guatemala and, using DNA analysis, the police were able to identify that baby as Angela.

Some of the samples collected by DNA-Prokids are analyzed at the University of North Texas Health Science Center in Fort Worth — the same group that’s collaborating with the Dallas police on the Prostitute Diversion Initiative. Katsanis focused her commentary on these two programs, she says, because they’re examples of partnerships between government and academia. The academic scientists “are holding the information, and handling it, and then returning it back to the law enforcement community,” she says.

But what Katsanis would really like to understand, she says, “is how this could be done outside of government, especially when we’re collecting from innocent people.”

Take those Texas prostitutes, who will never personally benefit from their DNA testing. The police have good reasons for this. “They have to keep a chain of custody. They have to protect those samples because those samples might become evidence,” Katsanis explains. And that’s obviously important. But if non-government parties — human rights organizations, for example — knew more about the possible uses of DNA testing, perhaps they could also get involved at the time of collection, and perhaps set up a system of analysis and storage that’s separate from law enforcement.

That’s probably a fanciful scenario, at least for now, Katsanis says. “The most challenging aspect is trying to figure out a way to infiltrate the community that is working directly with trafficked victims, for them to even be aware that this is an option.”

This comment really surprised me. Why not just reach out to the big NGOs and foundations and tell them all about DNA? ”I think there’s a distrust among the care providers that DNA is a law enforcement tool and not a victim advocacy tool,” she says.

A lot of issues swirling around DNA boil down to trust, don’t they? You might trust a consumer genetics company to keep your DNA information secure, for example, or you might trust a medical center to store your baby’s umbilical cord blood. But do you trust the government with your DNA?

I asked Katsanis whether she would ever contribute a DNA sample to a U.S. government database. She replied with a swift and certain, “No,” and then told me a story about the day she gave a lecture on DNA to some police officers in Greensboro, North Carolina.

“After I lectured to them, I said, ‘What do you guys think of a universal database? Should we just put everybody in it?’,” she recalls. “They said, ‘You mean me, too?’ and I said, ‘Yeah, you too.’ And they said, ‘Oh no, not at all, not ever. I don’t trust the police. I don’t trust us to not misuse that DNA’.”

*

Find out more about human protections and DNA (and download full case studies of the Prostitute Diversion Initiative and DNA-Prokids) at Katsanis’s group’s website.

I certainly do my share of gene’splaining. But for all the buzz given to the studies that uncover telltale genes, rarely mentioned are the most obvious and familiar examples of how genes aren’t destiny: identical twins. They share the same genome and, usually, the same parents, same neighborhood, and same food. And yet, as anybody who’s ever met a pair knows, they are not the same person. Why?

“Ten years ago the prevailing theory was that there must be systematic differences in their environments,” says Eric Turkheimer, a professor of psychology at the University of Virginia. One twin is favored by her mother, say, or is bullied in school, or catches fewer colds. But studies looking for big, non-shared environmental influences have come up short. As Turkheimer wrote in a fascinating commentary in 2011: “Exactly what the nonshared environment consists of has been a matter of mystery and controversy for some time.”

This is a tough thing to study in people. After all, scientists can’t pluck a pair of newborn identical twins from the arms of their mother, raise them for years in absolutely identical environments, and watch how they diverge.

Scientists can do that with mice, though, and now they have. In today’s issue of Science, neuroscientist Gerd Kempermann and colleagues report that genetically identical mice raised in the same environment show striking differences in their brains and exploratory behaviors. What’s more, these individual differences — individual personalities, you might say — become more and more pronounced over time.

The “enriched” environment. From Freund et al., Science 2013.

The researchers started with 40 identical, inbred female mice, and implanted radio-frequency identification tags in their necks. They housed the animals for three months in what must be the mac daddy of all rodent cribs: a 6-foot-square, 6-foot-tall, five-level enclosure, outfitted with acrylic glass tubes, nesting boxes, plentiful food and water, and a sprinkling of plastic flower pots, cardboard pieces, wooden scaffolds, and other toys.

This “enriched environment” also had antennas throughout that tracked the precise movements of the mice. The researchers calculated the animals’ roaming entropy, or RE, which is the probability that a mouse is located at any given location at any given time. RE is related to physical activity, but not exactly the same. “On a treadmill your roaming entropy is much lower than on a forest trail,” Kempermann explains. But RE isn’t only about territory coverage, either. Flying from New York to Los Angeles, despite covering a huge territory, would be a low RE because you don’t cover the space in between. So: A high RE means the mouse covers a lot of territory and covers it thoroughly.

By Jodi Cobb, National Geographic

The scientists also tracked how the animals’ brains changed over the three-month period. They measured neurogenesis, or the birth of new neurons in the hippocampus, a region important for learning and memory. Neurogenesis is a useful measure of brain plasticity for two reasons. First, it’s very responsive to environmental changes. Second, it’s quantifiable. “Neurons, we can count,” Kempermann says.

When he was a postdoc in Rusty Gage’s lab at the Salk Institute, in California, Kempermann reported that adult mice given access to a running wheel made twice as many new neurons than did mice with no wheel. Within the running group, of course, some individuals used the wheel more than others. “We started to wonder whether there might be individual differences in the response, even if the talent, the genetic make-up, was the same,” says Kempermann, who now works at the German Center for Neurodegenerative Diseases in Dresden*.

And that’s exactly what his new study found. The mice showed individual differences in RE right from the get-go, but they became far more different from one another as time went on. The study also found a strong association between RE and neurogenesis: Mice with the most extensive exploratory behavior showed the most neurogenesis.

“What this study objectively and clearly shows is that the ‘nature vs. nurture’ tension goes right down to the level of brain circuits,” says Sam Pleasure, a professor of neurology at the University of California, San Francisco, who was not involved in the work.

What the study doesn’t yet explain, though, is the biological mechanism driving these individual differences. Environmental changes can affect DNA methylation, an epigenetic mark that affects how genes are expressed. So mice with lower REs may carry different methylation signatures than those with higher REs, for example. “If the study had gone that one step further, it would have been even more significant,” Pleasure says. Kempermann agrees, and plans to look for possible epigenetic explanations in future experiments.

By Jason T. Ramsay, via Flickr

We will never know how the same experiment would play out with people, but the findings make intuitive sense, given what we know of identical twins. The data might also explain some intriguing differences in human intelligence, according to Turkheimer. Despite the fact that intelligence has a strong genetic component, “people have been getting smarter on IQ tests for the last century,” he says, a phenomenon known as the Flynn effect, after James Flynn, who first documented it.

Flynn and economist William Dickens proposed an explanation based on behavioral feedback loops. The environment after the industrial revolution became more cognitively demanding, and in response, people adapted, leading them to change the environment so that it’s even more demanding and requiring higher intelligence. ”This study suggests that changes of that kind might actually have a neural basis, which is a very exciting possibility,” Turkheimer says.

Turkheimer describes this whole idea quite beautifully in that 2011 commentary (which, it’s worth saying again, is really worth a read):

“The nonshared environment, in a phrase, is free will,” he writes. “Not the kind of metaphysical free will that no one believes in anymore, according to which human souls float free above the mechanistic constraints of the physical world, but an embodied free will, tethered to biology, that encompasses our ability to respond to complex circumstances in complex and unpredictable ways and in the process to build a self.”

Who we are, in other words, is our genes, yes, and it’s our environment, yes — but also what we do with them.

*

The study was a joint effort of the German Center for Neurodegenerative Diseases in Dresden, the Center for Regenerative Therapies Dresden, and the Max Planck Institute for Human Development in Berlin.

If you’re interested in further reading on this subject, check out National Geographic’s feature on twins, or a story I wrote for New Scientist about scientists using these sorts of feedback loops to design intelligent robots.

(Caveat up front: Some studies have found that exercise does not improve cognition. I will be conveniently ignoring those in this post and in life.)

Exercise: Good now, good later!

The mental benefits of exercise begin while you’re doing it and continue in the hours afterward. Take two studies from the mid-90s that tested volunteers before, during, and after moderate-intensity stints on an exercise bike. In one study, students watched a screen while biking. The screen showed a square filling up with a color, and the volunteers’ task was to push a joystick button as soon as the square was full. Reaction times were significantly faster while biking than at rest.

In the other study, endurance athletes took a series of cognitive tasks before and immediately after reaching 75 percent of their maximum energy capacity on the bike. After exercising, the athletes showed much better scores on the famous Stroop test, in which they were shown color words (like red, blue, and green) but were asked to name the color of the letters in the word rather than read the word. It’s a tough test (try it!), and a standard measure of cognitive flexibility and executive function.

What if you don’t care about your mental abilities later today, you whine? Then exercise for your future brain. A 2009 study of more than 3,000 people showed that exercise habits in middle age can influence the risk of dementia some 30 years later. The researchers found that people who do regular exercise (such as playing sports) or light exercise (such as gardening or walking) in their 40s are significantly less likely to develop dementia three decades later compared with those who don’t exercise at all. (The study controlled for lots of other factors, too, including age, sex, education, diet, smoking, drinking alcohol, and body mass index.)

That’s no reason, mind you, for young people to take it easy. Another large Swedish study found that changes in cardiovascular fitness (again measured by stationary bike) between age 15 and age 18 predict cognitive performance scores at age 18.

Exercise: Curbs brain shrinkage!

If you’re not convinced by those behavioral studies, how about a neurobiological angle: Some research shows that exercise curbs the brain shrinkage that naturally happens with age. One group found that people who exercised (defined as sweating for at least 20 minutes at least twice a week) in middle age had more gray matter (brain tissue where neurons live) 21 years later compared with sedentary people. This shrinkage protection was especially prominent in the frontal lobes, whose activity is important for working memory, planning and attention.

If you’re already in your senior years, it’s not too late to jump on the exercise train. A few years ago, researchers studied 59 people aged 60 to 79, putting half in an aerobic exercise program and the other in a stretching program. After six months, those in the aerobic training showed increased gray matter and white matter (the connections between brain regions) compared with the stretching group. In a similar study of older adults, another team found that cardiovascular training improves spatial memory and slows down age-related shrinkage in the hippocampus, a region important for memory, by one to two years.

Exercise: Any type is good!

All of the aforementioned studies focus on aerobic exercise — the stuff that gets your heart beating and sweat rolling. That seems to be the most effective type, but if you’re just not up for that kind of exertion, I’ve got some other studies for you.

Why not try a low-intensity gymnastics workout? It boosts memory scores just as well as a more intensive workout, according to one study. How about lifting free weights twice a week? Improves scores on the Stroop test. Even “coordination training,” which focuses on eye-hand coordination and leg-arm coordination, improves performance on tests of visual attention.

And with that selective and highly unscientific review*, I’m officially out of excuses.

–

*If you’d like more, um, real science, check out this report just published in Neuroscience and Biobehavioral Reviews.

In the 1940s, geneticist Barbara McClintock of the Cold Spring Harbor Laboratory in New York wanted to know: Why is it that some kernels show an uneven splattering of color? If the DNA in every cell in each kernel contains the same pigment gene (or genes), then why isn’t that color expressed the same way in every cell?

As McClintock would discover (and, three decades later, win a Nobel Prize for), the color variation in maize comes from transposons, or so-called jumping genes. These stretches of DNA hop out of their original spot in the genome and then wedge themselves in another, random place. When they land, they may disrupt the activities of nearby genes, including pigment genes. The jumping patterns are different in every cell, thus explaining the color variability.

Ever since McClintock’s big discovery, two ideas have dominated the scientific literature on jumping genes, notes Josh Dubnau, a neuroscientist at Cold Spring Harbor. One is that transposons are, in a sense, friendly. For example, as I wrote about a couple of weeks ago, a recent study found that jumping genes are more active in some types of neurons than others, suggesting that the brain has evolved ways of using these elements for its own (normal, healthy) specialization.

The other idea is that, while transposons may be useful in certain circumstances, they’re usually parasites. Studies have shown that when transposons jump in stem cells that become sperm or egg cells, for example, “they can destroy the germline. You can get animals that are completely sterile simply because a transposon has gone rogue,” Dubnau says. “This is the dark side of transposons.”

Dubnau has provided another example of transposon terror in a study published earlier this month in Nature Neuroscience. His team found that in normal fruit fly brains, jumping genes accumulate and become more active with age. What’s more, mutant flies with too many transposons show long-term memory problems and die earlier than normal flies.

McClintock’s maize studies concerned jumping genes that get cut out of the genome and pasted elsewhere. But these ‘DNA transposons’ seem to be inactive in humans, Dubnau says. His study focused instead on a type of jumping gene that is active in people. Called ‘retrotransposons’, these genes are first copied and then the copy is pasted into a new spot.

One reason to think of retrotransposons as foes is that “we have a really, really elaborate, sort of like an innate immune system against them,” Dubnau says. “We as animals put a lot of genomic effort into silencing them.”

Take, for example, our argonaute family of proteins, which can latch on to jumping genes and shut them down. Dubnau’s team genetically manipulated one of the argonautes, AGO2, so that the transposons it regulates would be, in the words of the study, “unleashed prematurely” in young flies. These young’ins show dramatic memory loss by the time they’re 20 days old, less than halfway through the 50-day life of a normal fly. The mutants die around 30 days.

Josh Dubnau, ready to dig into that famous maize. Photo by Scott Waddell.

The study hasn’t quite proven that transposon build-up causes these memory problems; it could be that the jumping genes accumulate as a consequence of some other aspect of the accelerated aging, Dubnau says. “The idea that transposons jumping into somaitic tissue causes disease is still new and unproven.”

Still, some of his other work bolsters the idea that jumping genes are the culprits. In a study published last year, his group showed that jumping genes normally bind to TDP-43, a protein that has been linked to frontotemporal dementia and Lou Gehrig’s disease. In postmortem brain tissue from people who had frontotemporal dementia, however, the transposons do not bind to TDP-43. “We interpret that as being evidence that the TDP-43 protein normally helps to silence transposons, but that in patients it somehow loses its ability to bind to and silence them.”

With only 70 years down since that famous maize discovery, there’s much more unknown than known about jumping genes. In fact, the very question of whether they’re our friend or foe may be terribly naive. “You could have some transposons that are jumping in a nice regulated way during development and providing some function, and then those same transposons could become evil doers as the animal ages,” Dubnau says.

“We’ve had these things in our genomes for millions of years. Anything that can be used by evolution will be used by evolution.”

So it was refreshing, at the Cognitive Neuroscience Society meeting last weekend, to hear about a line of emotion research that does have direct clinical relevance. More than half of all people with psychiatric disorders have trouble with emotion regulation, the actions or thoughts (conscious or unconscious) we make in order to keep our feelings in check. People who have trouble regulating their emotions might have angry outbursts in response to what others would consider a minor annoyance, for example, or intentionally avoid a place where they once experienced a traumatic event, or be completely debilitated during causal conversations by fear of what the other person thinks of them.

Psychologists have long known of behavioral strategies that help people regulate their emotions. The scientists I heard at the meeting have been using brain scans to try to figure out why these strategies work so well.

In the first strategy, called cognitive reappraisal, you deliberately try to change your interpretation of a situation. Matt Lieberman, a psychology professor at UCLA, introduced the concept with this disturbing photo:

“Your first reaction might be, ‘Oh, I feel so bad because this lady was clearly beaten and mugged’,” Lieberman said. Naturally, that might make you feel sad or angry.

“But then reappraisal might kick in. And you might remember that, wait, isn’t that Gene Simmons of Kiss? And wait, I heard that he actually had a face lift. So really this is just something he did to himself, he’s just recovering from surgery,” Lieberman said to a chuckling crowd. After reframing the picture in the new context, he explained, your sadness is likely to fade.

Reappraisal is a core part of cognitive behavioral therapy, the talk sessions with a psychologist or counselor that help treat many people with anxiety and mood disorders. James Gross, a psychology professor at Stanford and another speaker at the meeting, has been investigating the biological basis of reappraisal for two decades. His studies have shown that when experiencing something unpleasant, reappraisal not only makes you feel better, but decreases your blood pressure, activates the front part of the brain and dials down its emotional circuits.

In one of the first neuroimaging studies to look at reappraisal, published in 2002, Gross’s team showed healthy people a series of unpleasant photographs, such as a woman crying outside of a church. On some trials, the researchers instructed participants to think of a way to interpret the pictures in a more positive light. So the woman outside of the church, for example, could be crying after a wedding rather than a funeral. During this reappraisal, participants’ brains showed increased activation in the dorsomedial prefrontal cortex, a region in the outer layers of the brain that’s involved in self-processing and emotional awareness, and decreased activity in the amygdala, which is important for emotional and fearful responses, compared with trials when they were told to simply look at each photo without trying to change their feelings.

In later work, Gross found that these brain systems involved in reappraisal seem to be impaired in people with social anxiety disorder (SAD). This condition, characterized by an intense fear during social interactions and negative self-beliefs, is surprisingly common, with a lifetime prevalence of 12 percent. In one study, Gross’s team scanned the brains of people with SAD while negative statements, such as NO ONE LIKES ME or I’M A LOSER, flashed on a screen in front of them. When the belief flashed in white letters, they were instructed to focus on how true it was for them. When it flashed in green, they were told to reappraise it in a way that made it less negative. After each sentence they were asked to rate their emotions.

Surprisingly, like healthy controls, people with SAD were able to dial down their emotions after reappraisal, the study found. And like controls, their brains activated the prefrontal cortex and turned down the amygdala. But it took more time. “The socially anxious people, although they get there eventually, are less able to actively and quickly recruit these systems,” Gross said. When some of the same patients then went through 16 sessions of cognitive behavioral therapy, their brain responses to reappraisal got faster, suggesting that reappraisal is the “active ingredient” in this kind of treatment, Gross said.

Learning how to reframe a negative thought is an explicit, conscious technique. Lieberman’s work, in contrast, has focused on a emotion regulation strategy that we all do everyday, usually without noticing it. The jargony name of the strategy is “affect naming,” but it boils down to simply putting your feelings into words. With reappraisal, you’re always trying to change the meaning of something. So reappraisal of the Gene Simmons photo might be “This isn’t as bad as it looks.” But affect naming might be as simple as “This person looks unhappy,” or “Looking at this person makes me feel queasy.”

Philosophers have long recognized the benefits of affect naming. Spinoza wrote in 1675 that “An emotion, which is a passion, ceases to be a passion, as soon as we form a clear and distinct idea thereof.” And William James, in 1890, wrote of emotions that “The act of naming them has momentarily detracted from their force.”

Lieberman and others have shown in modern-day laboratories that this simple act of naming produces nearly all of the same psychological and neurobiological effects as reappraisal. For example, in 2007 he published a study in which healthy participants looked at emotional faces inside of a brain scanner. On some trials the volunteers were asked to choose which emotion was on the face (eg, scared or angry) and on other trials they were asked to choose the most appropriate gender (eg, Sam or Helen). On the emotion trials (where participants are essentially naming the negative emotion associated with the picture) their brains showed lower responses in the amygdala and increased activity in the prefrontal cortex.

Affect naming also has clinical relevance, Lieberman says. Last year his team published a study showing how affect naming can add to the positive effects of exposure therapy, in which people who are afraid of something receive repeated safe exposures to it. The researchers brought college students who were afraid of spiders into a room and had them sit two feet from a live tarantula covered by a screen. Some people got only this exposure to the spider, while others got the exposure plus another kind of therapy: reappraisal, distractions or affect naming. Compared with those in the other groups, participants who were asked to simply talk about their arachno-anxiety were more willing to get closer to the spider a week later. “And the more negative their labels are, the closer they’re willing to get,” Lieberman said.

What’s maybe most interesting about all of Lieberman’s findings, though, is that people seem to have no idea that affect labeling makes them feel better. When given surveys after the testing is over, participants tend to think the opposite: that naming their emotions draws attention to negative feelings and amplifies them. That’s certainly what I thought before hearing these talks.

This finding has interesting implications for behavioral therapies, he says, because affect naming might be easier to implement than reappraisal. “People don’t mind saying what they’re feeling, sometimes they get defensive about something telling you to think differently than you already do,” he says. And although affect naming is probably involved in every kind of talk therapy, “it’s never really considered an end in itself,” he says. Maybe it should be.

*

Top image by Kendall Gelner via Flickr

“This piece of music came on, and something just happened,” Salimpoor recalls. “I just felt this rush of emotion come through me. It was so intense.” She pulled over to the side of the street so she could concentrate on the song and the pleasure it gave her.

When the song was over, Salimpoor’s mind raced with questions. “I was thinking, wow, what just happened? A few minutes ago I was so depressed, and now I’m euphoric,” she says. “I decided that I had to figure out how this happened — that that’s what I’m going to do with the rest of my life.”

Music moves people of all cultures, in a way that doesn’t seem to happen with other animals. Nobody really understands why listening to music — which, unlike sex or food, has no intrinsic value — can trigger such profoundly rewarding experiences. Salimpoor and other neuroscientists are trying to figure it out with the help of brain scanners.

Yesterday, for example, researchers from Stanford reported that when listening to a new piece of classical music, different people show the same patterns of synchronized activity in several brain areas, suggesting some level of universal experience. But obviously no one’s experience is exactly the same. In today’s issue of Science, Salimpoor’s group reports that when you listen to a song for the first time, the strength of certain neural connections can predict how much you like the music, and that these preferences are guided by what you’ve heard and enjoyed in the past.

After Salimpoor had the car epiphany, she rushed home to her computer and Googled “music and the brain.” That led her to graduate school at McGill University, working in the lab of neuroscientist Robert Zatorre.

A few years ago, Salimpoor and Zatorre performed another type of brain scanning experiment in which participants listened to music that gave them goosebumps or chills. The researchers then injected them with a radioactive tracer that binds to the receptors of dopamine, a chemical that’s involved in motivation and reward. With this technique, called positron emission tomography or PET, the researchers showed that 15 minutes after participants listened to their favorite song, their brains flooded with dopamine.

The dopamine system is old, evolutionarily speaking, and is active in many animals during sex and eating. “But animals don’t get intense pleasures to music,” Salimpoor says. “So we knew there had to be a lot more to it.”

In the new experiment, the researchers used functional magnetic resonance imaging (fMRI) to track real-time brain activity as participants listened to the first 30 seconds of 60 unfamiliar songs. To quantify how much they liked the music, participants were given the chance to buy the full version of each song — with their own money! — using a computer program resembling iTunes. The program was set up like an auction, so participants would choose how much they were willing to spend on the song, with bids ranging from $0 to $2.

You can imagine how tricky it was to design this experiment. All of the participants had to listen to the same set of never-heard-before songs, and yet, in order to get enough useable data, there had to be a reasonable chance that they would like some of the songs enough to buy them.

Salimpoor began by giving 126 volunteers comprehensive surveys about their musical preferences. “We asked them to list all of the music they listen to, everything they like, everything they’ve ever bought,” Salimpoor says. She ultimately scanned 19 volunteers who had indicated similar preferences, mostly electronic and indy music. “In Montreal there’s a big indy scene,” she says.

To create the list of unfamiliar songs, Salimpoor first looked at songs and artists that showed up on many of the volunteers’ surveys. She plugged those choices into musical recommendation programs, such as Pandora and iTunes, to find similar but less well-known selections. She also asked people who worked at local music stores what new songs they’d recommend in those genres.

Here’s a sampling of 3 songs from the final list of 60:

The brain scans highlighted the nucleus accumbens, often referred to as the brain’s ‘pleasure center’, a deep region of the brain that connects to dopamine neurons and is activated during eating, gambling and sex. It turns out that connections between the nucleus accumbens and several other brain areas could predict how much a participant was willing to spend on a given song. Those areas included the amygdala, which is involved in processing emotion, the hippocampus, which is important for learning and memory, and the ventromedial prefrontal cortex, which is involved in decision-making.

The data are “compelling,” especially because the study objectively quantified the participants’ preferences, notes Thalia Wheatley, a psychology professor at Dartmouth College who has studied links between music, motion and emotion. The emphasis on connectivity between regions, rather than any particular region by itself, is also intriguing, she says. ”Cortical activity alone does not predict bid value. Hooking up the temporal and evaluative processing in the cortex with the (more primitive) reward areas appears to be the key.”

So why is it that one person might spend $2 on a song while another pans it? Salimpoor says it all depends on past musical experiences. “Depending on what styles youre used to — Eastern, Western, jazz, heavy metal, pop — all of these have very different rules they follow, and they’re all implicitly recorded in your brain,” she says. “Whether you realize it or not, every time you’re listening to music, you’re constantly activating these templates that you have.”

Using those musical memory templates, the nucleus accumbens then acts as a prediction machine, she says. It predicts the reward that you’ll feel from a given piece of music based on similar types of music you’ve heard before. If you like it better than predicted, it registers as intense pleasure. If you feel worse than predicted, you feel bored or disappointed.

“New music is presumably rewarding not only because it fits implicitly learned patterns but because it deviates from those patterns, however slightly,” Wheatley says. But this finding leads to new questions. “It just made me wonder whether people have different preferences or tolerances for how much a new song deviates from the well-worn path of previously heard music structures.”

There are lots of other questions for future studies to probe. How does our brain make those musical templates? How long do we have to listen to a song before we know whether we like it? Why did my sister and I have such drastically different musical tastes growing up, even though our exposures were pretty much the same?

But for now the study has given Salimpoor a new way to think about what happened to her that day in the car. ”That day, it all seemed like such a big mystery — what the heck is happening in my brain?” she says. But if she heard the song again today, she’d be able to tell a reasonable story of her mind’s workings.

“I’d be like, oh my god I just released dopamine, and my nucleus accumbens is now communicating with the superior temporal gyrus, and that’s pulling up some other memories of when I was 12 and playing the violin,” she says, laughing. “And then that’s linking it to my visual centers, so I can imagine this perfect synchronized orchestra and me playing a violin in there. And I’d be predicting the next sounds from each instrument in the orchestra, and the whole orchestra, so it’s a local and global prediciton going on at the same time.”

Music, she says, is an intellectual reward. “It’s really an exercise for your whole brain.”

A couple of weeks ago, researchers reported that overweight people show a distinct chemical profile in their breath — too much hydrogen and methane — that could be due to a particular species of bug in their gut. Then another group found that in mice, gastric bypass surgery changes the microbial make-up of the gut, and this shift might explain the animals’ subsequent weight loss.

Both of these studies, like many others published in the last few years, suggest that there’s some kind of connection between gut microbes and weight. The latest report, out today in the Proceedings of the National Academy of Sciences, digs a bit deeper, analyzing how bacteria and fatty foods interact in the mouse gut.

More provocatively: The new study uncovers a natural enzyme that might prevent — or even reverse — obesity in people.

Trillions of bacteria lurk in our digestive tract, eating our food and helping us digest it in return. In that cozy space, the bugs have a remarkably copacetic relationship with our immune system (which, after all, doesn’t typically get along with bacteria). But if the microbes travel outside of the gut, it can cause trouble.

The cell walls of gram-negative bacteria hold a molecule called lipopolysaccharide. More commonly known as endotoxin, the molecule triggers the human immune system and can be extremely dangerous in large quantities. “When people have very bad infections, they can get very high levels of endotoxin in their blood and get sepsis or die,” says Richard Hodin, a professor of surgery at Harvard.

Even low levels of endotoxin can be harmful. In 2007, a study led by Rémy Burcelin at INSERM in Toulouse, France, showed that when mice eat a high-fat diet, it (somehow) increases the amount of endotoxin in their gut. Burcelin’s experiments also suggested that endotoxin causes intestinal inflammation, which in turn makes the gut more permeable, allowing endotoxin to leak into the blood supply and further aggravate the immune system. Over time, mice carrying excess endotoxin develop chronic inflammation, insulin resistance and obesity — all features of metabolic syndrome, which affects more than 20 percent of people in the U.S. and ups the risk of heart disease, stroke and diabetes.

More recent studies have shown that in people, too, eating fatty foods induces a dramatic spike in blood endotoxin.

So: Too much endotoxin is bad. The new study focuses on a natural gut enzyme — called intestinal alkaline phosphatase (IAP) — that helps keep endotoxin in check.

IAP has been studied for several decades for its role in helping the body absorb fat. When rats eat a fatty meal, IAP levels shoot up in their blood and lymph. When the animals don’t eat anything, they stop making IAP. And when mice lacking the IAP gene go on a long-term high-fat diet, they get very fat.

IAP is found on cells that line the small intestine. But researchers are just beginning to understand what it does there, Hodin says. “It’s only in the past five or so years that we’ve started to figure out that this enzyme primarily functions as a protective mechanism against the bacteria in the gut.”

In 2010 Hodin’s team reported that in cells cultured in the lab, IAP can detoxify bacteria, effectively blotting out endotoxin. In the new study, the researchers tested whether IAP could also curb the detrimental effects of endotoxin in living animals.

The researchers found that mice lacking IAP have leaky guts, as well as excess endotoxin and inflammatory molecules in their blood. The knockout animals are also obese and have insulin resistance, a sign of diabetes.

The team then looked at the effects feeding mice IAP as a supplement to a high-fat diet. A daily dose of IAP (it’s a powder that dissolves in the animals’ drinking water) for 11 weeks prevented all of the problems that develop in mice eating the high-fat diet alone — insulin resistance, leaky gut, blood endotoxin, inflammation, and weight gain.

In yet another set of experiments, the researchers fed mice a high-fat diet and allowed them to fully develop metabolic syndrome and obesity. Then they gave them the IAP supplement for six weeks. In these animals, IAP reduced endotoxin levels, inflammation and glucose intolerance. If the fat mice had taken the supplement for a longer period of time, their condition may have reversed even more, Hodin says.

Like all mouse studies, it’s unclear whether the same patterns would hold in people taking IAP. Hodin’s team is working on a formulation of the enzyme that can be tested in people in the next couple of years.

Unlike most obesity drugs, toxicity and side effects are not likely to be a problem for this substance. “We think it’s going to be safe because it’s an enzyme that’s naturally occurring in our intestines anyway,” Hodin says. One small clinical trial in Europe used IAP to treat ulcerative colitis and found no side effects of the enzyme, he adds.

A bigger question is how many people with metabolic syndrome or obesity might benefit from IAP treatment. “There’s roughly 400 million people with diabetes and even more with obesity, and they don’t all have the same metabolic syndrome and types of diabetes. Some might have a problem with the IAP system and others might not,” says Burcelin, whose team found the link between a fatty diet and endotoxin. “We probably need to identify biomarkers first to identify which patients should be treated with that type of strategy or not. But I think that it could work.”

Other scientists are curious about the mechanism that allows IAP to work. Hodin’s hypothesis is that it works by somehow blocking the passage of endotoxin through a leaky gut. But there are alternative explanations, notes Peter Holt, a gastroenterologist and senior research associate at the Rockefeller University who has studied the relationship between fat and endotoxin. “It could be that IAP changes the gut bacteria in such a way that less endotoxin is formed,” Holt says. If that’s the case, he adds, then there might be other ways to adjust the bacterial populations of the gut that wouldn’t require high doses of IAP.

Regardless of the mechanism, though, the new study is part of an exciting wave of research on the (still largely mysterious) interactions between our food, immune system and microbial residents. Just yesterday, a study in Nature Medicine reported that when eaten in large quantities, an ingredient in red meat causes gut bacteria to produce a chemical that accelerates heart disease. As my fellow Phenomena blogger Carl Zimmer wrote this morning, despite the fact that nobody really understands the underlying biology, these discoveries have fueled a microbiome industry of yogurts, pills and creams already worth $8.7 billion.

“We’re at the beginning of a whole age of altering microbiota at will,” Holt says. “It’s bound to happen in the next few years. And to my mind that’s the most interesting and potentially powerful experimental manipulation in humans that’s on the horizon.”

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In addition to the scientists quoted above, many thanks to Pauline Lund of the University of North Carolina at Chapel Hill for sharing her thoughts on the new study.

The entire concept of epigenetics is being highjacked today for the Left’s eternal propaganda of neo-Lysenkoism — that “Nurture over Nature”, environment and not heredity, is what most significantly determines human qualities.

It’s essential to understand that the “methylome” is NOT — as the Left would like to give us the impression — an alternate kind of biological code created by the environment. It is not a competing genome that can overrule inherited DNA. It’s only a part of the chemical apparatus produced BY the DNA, to operate the cell.

I wouldn’t bother giving Lauren any attention except that her comment really gets under my skin. I never said or implied that environmental influences determine human qualities, for one thing. But worse than that, implicit in her remark is the opposite claim, which is just as insidious and, unfortunately, much more commonly argued: that genes determine our fate, that the genome is fixed, that environments don’t matter.

I’ve ranted before about the perils of genetic determinism and how it has contributed to an overblown fear of all things genetic. Where does the idea come from? And why does it have such a stronghold on our culture? Should I blame social Darwinism? Nazis? Gattaca? Or maybe it starts in biology class.

I’d guess that the vast majority of people, if they think about the genome at all, think of it as a static, abstract code, a string of letters that you’re born with and can’t do anything about. That’s sort of true, but sort of not true, and this complexity is something I tend to harp on in blog posts.

The super-long DNA ‘code’ is a physical molecule. It wraps around itself in a certain way so that it can fit into each of our cells. That wrapping affects which genes are turned on and made into proteins and which stay silent. DNA is littered with methyl groups, and these, too, turn genes on and off. And yes, Lauren, methylation itself is genetically encoded, leading to distinct ‘methylation landscapes’ in different tissues. But methylation is also influenced by environmental exposures, diet, and age.

Even if you put those epigenetic influences aside, the underlying genome isn’t fixed. DNA mutations frequently crop up during cell division, making the daughter cell and all of its progeny genetically distinct.

And then there are jumping genes, the subject of a cool neuroscience paper that came out yesterday in Science. Nearly 45 percent of the human genome is made of transposons, or pieces of DNA that can ‘jump’ randomly around the genome. Sometimes jumping genes use a cut-and-paste approach, other times a copy-and-paste, and these insertions can cause coding disruptions that can contribute to disease.

The new study shows that transposon activity is quite variable from one cell type to another. Analyzing the brains of adult fruit flies, the researchers showed that jumping genes are particularly active in ‘alpha-beta neurons’, which are important for processing smell-related memories. Many of these jumping DNA pieces insert themselves near or inside of active genes, likely affecting their function. These “disruptive insertions,” the researchers speculate, could accumulate throughout life, ultimately contributing to memory decline (or, if you’re into hyperbole, to fly “personalities“).

So why am I so obsessed with the dynamic genome? Mostly because it’s fascinating stuff. But I also wish that more people appreciated the unbelievable complexity of DNA and its dances with an ever-changing environment. If you think of the genome as moving and flexible, then it’s hard to fall into the trap of genetic determinism. Isn’t it?

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Photo by Jorge Fardels, via Flickr

Charcot was also an expert pathologist. After performing autopsies on several of these patients, he named their disease amyotrophic lateral sclerosis: muscle atrophy (amyotrophic) with scarring (sclerosis) in part of the (lateral) spinal cord. The scarring came from the death of motor neurons, large cells in the spinal cord whose long branches reach out to muscles and control their contractions.

More than a century has passed, and still the only way to definitively diagnose ALS — known as Lou Gehrig’s disease here in the U.S. and as Charcot disease in France — is with an autopsy showing the widespread disappearance of motor neurons in the spinal cord and the brain. It’s not surprising, then, that the vast majority of research on the roots of ALS has focused on motor neurons. But in the past few years, scientists have found hints that several types of glia, the under-appreciated cells typically described as “support cells” for neurons, may also be cellular culprits in the disease.

“What’s maybe a misnomer in the field is that people think that just because the motor neurons die, that that’s the source of disease,” says Dwight Bergles, a professor of neuroscience at Johns Hopkins University. “But there are multiple cell types that contribute.”

In today’s issue of Nature Neuroscience, Bergles and his colleagues find that oligodendrocytes — glia that wrap around the branches of motor neurons, creating a fatty sheath that gives the neuron energy and insulates its electrical messages — die in a mouse model of ALS even before the animals show symptoms of the disease. According to Bergles and others, the findings point to a possible new treatment strategy for many types of neurodegenerative disease: support the support cells.

“Neurons and glial cells have this intimate relationship in the nervous system, and neurons are absolutely dependent on glial cells for support,” Bergles says. “So obviously if you somehow could preserve the functions of these support cells, that could have benefit.”

Like so many scientific discoveries, this one began with a bit of serendipity. A few years ago, while working as a postdoc at the Vollum Institute in Portland, Oregon, Bergles was studying the normal activity of stem cells that give rise to oligodendrocytes. In a separate project, he was also looking at a common mouse model of ALS. “One day, just on a lark, we said hey, why don’t we look at the cells in the ALS tissue?” he recalls.

They found that in adult ALS mice, these progenitors, called NG2+ cells, divide rapidly in the same regions of spinal cord where motor neurons die. What’s more, as the disease progresses, the NG2+ cells make more and more oligodendrocytes. “We knew this was really unusual in an adult animal, so we thought there must be something happening to oligodendrocytes in this disease,” Bergles says.

The new study extends those findings in the same animal model, mice that make way too much of a mutant protein called SOD1. A small number of people with rare familial forms of ALS carry mutations in the SOD1 gene, and the SOD1 mice have several characteristic features of the disease, including muscle paralysis, motor neuron degeneration and early death.

Previous studies by Bergles’s colleague Don Cleveland of the University of California San Diego had found that removing the mutant SOD1 protein from specific types of glial cells, including microglia and astrocytes, slows the progression of disease. This suggests that when the gene’s function is messed up in these glial cells, it somehow exacerbates the disease. In the new study, Bergles and Cleveland found the same thing for oligodendrocytes. They report that in ALS mice, oligodendrocytes are damaged even before the mouse shows overt symptoms. What’s more, removing the mutant protein only from NG2+ cells significantly delays the onset of disease and prolongs the animals’ survival.

Like all studies that use this popular mouse model (or any mouse model), it’s unclear whether the findings extend to people with ALS. Bergles’s team showed that oligodendrocytes look abnormal in postmortem brain and spinal cord tissues from of people who died of ALS. Still, because glia are known to react to all sorts of problems in the brain, it’s hard to tease out cause and effect.

“It’s a very elegant and potentially interesting observation but for the moment it’s just correlative,” notes Serge Przedborski, a professor of neurology at Columbia University who has studied the role of astrocytes in the SOD1 model. Although the study doesn’t reveal any particular mechanism behind the oligodendrocyte oddities, Przedborski notes that a study published last year by Jeff Rothstein, another one of the new paper’s authors, could offer a clue.

In that work, Rothstein’s group found that oligodendrocytes hold molecules that transport lactate, a cellular energy source, and that disturbing these transporters leads to neuron death. The researchers also found that people with ALS and SOD1 mice lack these transporters. All of this suggests that oligodendrocytes are a key source of energy for neurons and that oligodendrocyte damage contributes to ALS progression.

If that’s the case, then the question of cause and effect might not matter in the development of treatments.

“For many, many years we all in the field of neurodegeneration have unfortunately looked at it from a very neuronal-centric view,” Przedborski says. “But neurons do not live or die in isolation. They’re surrounded by all these non-neuronal cells, and these cells are playing a key role, even before the disease starts.” This is most likely the case not only for ALS, but for Parkinson’s, Alzheimer’s, Huntington’s, and “any other neurodegenerative disorder you can think of,” he says.

It might also mean that the ALS field can look to other diseases for insights on treatment. Multiple sclerosis (MS), for example, stems from the destruction of oligodendrocytes, and several research groups have been developing MS drugs that promote the survival of oligodendrocytes. “So the thought now is that we could take some of the knowledge gained in the MS field and apply it to ALS,” Bergles says.

Here’s hoping. The treatment arsenal for ALS is empty. And the disease’s prognosis hasn’t much changed since Charcot described it 139 years ago. “As far as I know, there is no case in which all the symptoms occurred and a cure followed,” Charcot wrote. “Is this an absolute block? Only the future will tell.”

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For an interesting description of Charcot’s work on ALS, see this 2001 commentary by Columbia University neurologist Lewis Rowland.

Motor neuron image from Van Damme et al., PNAS, 2007.