Of Schizophrenic Mice and Men

He starts with a normal mouse, then changes a single gene to give it a “beautiful mind.” Though neuroscientist Akira Sawa will never know if the altered critters hear imaginary voices, he does know their brains look remarkably similar to those of the 1% of humans who have schizophrenia.  

Working at the Johns Hopkins University School of Medicine, Sawa has recently added a mutated gene—previously linked to schizophrenia—into the brains of mouse embryos. Remarkably, he found this stunted their development in the same way it does to many human schizophrenics. These modified mice could serve as models of the disease, to design and test new drugs. And further down the road, Sawa hopes to create more effective therapies using them in combination with ground-breaking stem-cell technology.  

Schizophrenia—a disease that causes hallucinations and emotional apathy—is usually diagnosed between age 15 and 30. Many researchers have thus assumed that it’s caused by environmental influences after birth, such as viral infections or psychological stresses. But in recent years, research on identical twins and autopsied brains of schizophrenics pointed to a genetic link.

Convinced of the genetic basis, Sawa looked for a gene or mutation that was reliably associated with the disease—a daunting task, as “more than 100 genes have been implicated in the disease but maybe 90 are junk.” He chose a gene called DISC-1 (Disrupted-in-Schizophrenia) for two reasons: “the other candidates were known genes with known functions…and only [DISC-1] has a clear disease-associated mutation.”  

To get mut-DISC1 into a developing mouse’s genome, Sawa’s latest study took advantage of the gene’s electrical properties. He placed a pregnant mouse in an electric field such that the negatively-charged mut-DISC1 was attracted to the positive end of the field, and thus forced into the embryo’s brain. Although Sawa said the technique only worked in one to five percent of cells, it was enough to dramatically change brain development.

In the mutated mice, the migration of neurons from the inside chambers of the brain to the outer layers of cortex was severely delayed. What’s more, an abnormal orientation of neurons in their brains matched that seen in the autopsied brains of human schizophrenics. Taken together, these results show that mut-DISC1 disrupts brain development and often leads to schizophrenia.

But mut-DISC1 isn’t a gene for schizophrenia. If “a mutation is in the same gene, but in a different place [within the gene],” Sawa said, “clinical manifestations can be very different.” In identical twins, for instance, sometimes only one gets the disease. “Even if they have the exact genome,” he said, “they may have different gene expression or one may catch a viral infection or…have different social stresses.”

The mouse models can be used right away to test new drugs; Sawa admitted he was funded by several pharmaceutical companies. But he’s more excited about a new treatment that uses human stem cells. Starting with a biopsy through a patient’s nose, neuronal stem cells could be harvested and then manipulated in the lab to replace the damaged ones. They “mimic neurodevelopmental features, even in an adult,” he said. “Here,” pointing to his nose, “they’re still young.” Though still three to five years away, Sawa has high hopes that using stem cell therapy in combination with the mouse models will ultimately “bridge bench to bed.”


Aliens Invade

Last month, five illegal aliens were caught in Queens, skulking in the brackish water of Meadow Lake. After positive identification, New York State authorities cut them with knives until they bled to death. But the government had no other choice. For unlike the illegal immigrants found working the fields of central California, these were alien fish, whose continued survival could lead to dire economic and ecological consequences.

The exterminated individuals were Northern snakehead fish (Channa argus argus), native to Asia. Also known as “Frankenfish,” the MO of these monsters comes straight from the annals of science fiction. Their heads, covered in snake-like scales that give them their name, also hold a mouth full of sharp fangs. Their torpedo-shaped bodies grow as long as 40 inches, as heavy as 15 pounds. They can breathe air, and “walk” on land using their pectoral fins. They’ll survive for several months under iced-over waters or even buried in mud banks. Scarier still is an insatiable and indiscriminate appetite—they’ll feast on anything on land or sea, from fish and frogs, to ducks, and even small mammals. Secretary of the Interior Gale A. Norton was apt to call them, “something from a bad horror movie.”

Yet the public has taken little note of the Queens incident, and the media has described it with tongue-in-cheek. In an August 9th  New York Times article, for instance, Anthony DePalma makes light of the problem, writing “Lady Liberty…might have a hard time getting at all gushy about some of the most recent immigrants to the city.”

This mockery of the snakeheads is unfortunate, and surprising, because this isn’t the first time the fish have reared their ugly heads. Just three years ago, a tourist bought a snakehead at a fish market in Manhattan’s Chinatown. (Sold for about $9 a pound, steamed strips of fish are often combined with ginger and scallions in sweet soup recipes. Cooks like them for their freshness, since they can survive up to four days out of water.) The man took his new pet back to Crofton, Maryland to raise it. But there was a problem: No matter how much it ate—up to 12 goldfish per day—it wouldn’t stop growing. When he finally dumped the beast into a small pond behind a local shopping center, he had no idea he was breaking a state law, or that his act could lead to an ecological disaster for the entire Chesapeake Bay.

Sadly, most Americans are not now and have never been aware of the dangers caused by the introduction of invasive alien species. For hundreds of years, Europeans and Americans who ventured abroad have shipped slaves, gold and, yes, biological booty back and forth from their native lands. Take one romantic, if not odd, Eugene Schieffelin. In the late 19th century, this wealthy contributor to New York theatre was determined to give the New World all of the birds ever mentioned in the works of Shakespeare. Most couldn’t survive the American habitat. But he released 60 pairs of starlings (mentioned by Shakespeare just once, in Henry IV: “I'll have a starling shall be taught to speak…”) that would propagate to become our most abundant and annoying bird species, pushing out natives like bluebirds and martins.

Granted, creatures from afar are often romantic, novel, exotic—it’s why everybody loves the zoo. So an earnest public might ask, why not bring them here? What’s the big deal?

According to an extensive 1993 report by the Office of Tribal Affairs (OTA), over 900 exotic, free-ranging species have caused ecological or economic harm in the United States. To understand why, consult evolutionary theory. Alien species, by definition, did not evolve in or for our specific ecosystem. Thus, when thrown into a new environment—with a new climate, new food sources, new competition, new prey—their behaviors are unpredictable. Unsurprisingly, many cannot survive at all. But others are superbly equipped to travel, thrive and even dominate their new surroundings.

Take that wretched Northern snakehead, for example. In its native Southeast Asia, it lives in irrigation ditches and rice paddies. After the rainy season, these trenches dry out and the fish must migrate to a wetter place. Hence, for thousands of years, the creatures with fins that allowed them to flop around on land are the ones that survived. Similarly adaptive systems evolved in the snakehead’s digestive system, where it has an air sac that allows it to absorb oxygen when it’s out of water. The snakeheads, thus falling into the category of invasive foreign species, are a North American ecosystem’s worst nightmare.  

The biggest ecological problem with invasive species is the loss of biodiversity. In the 1960s, a “walking” catfish from Sri Lanka was exported to a Florida fish farm. Within 10 years, the catfish had spread to 20 Floridan counties. In the decades since, up to 90%--that’s 4,000 pounds per acre—of the area’s fish kill has consisted of the catfish. In Australia, a similar invasion has caused the rapid decline of native frog populations. There, a deadly virus was introduced to Queensland and transmitted to frogs by an imported fish. The telling part: the fish was not sold for eating, but for ornament.  

Another negative effect of invasive species is the destruction of natural resources. The Siberian gypsy moth, an insect that strips the leaves from spruce, larch, and fir trees, and in large numbers thus poses a great threat to coniferous forests, is ranked in the top three of Russia’s biological pests. The OTA’s report divulged that thousands of raw logs imported to the United States from Siberia carried--guess what?—Siberian gypsy moths.  

And for those who scoff at the ecological consequences, perhaps they’ll sit up when they hear the situation affects their pocketbooks. Loss of biodiversity often translates into loss of money, and lots of it. The Australian Brown tree snake, accidentally introduced to Guam in the early 1950s, now thrives there with up to 13,000 snakes per square mile. The snakes, by crawling on power lines, have caused more than 1,200 power outages since 1978. Since its arrival in 1892, the Cotton boll weevil has cost the U.S. cotton industry $13 billion; Zebra mussels—introduced to the Great Lakes from Caspian Sea water dumped from a transatlantic ship—have clogged American pipes since at least 1988, demanding utility repairs to the tune of $3 billion.

So what ever happened to those snakefish dumped in the Maryland pond three years ago? Officials knew they had to be eradicated, for fear of their spread. Because they can “walk,” they could have left the pond, crawled a mere 75 feet to the Little Patuxent River, and from there invaded the Maryland river system and Chesapeake Bay. The pond could have been drained, except some of the fish would have inevitably buried themselves in the mud until they could make it to the Little Patuxent. Electroshock treatments didn’t work, due to dense vegetation in the pond. Traps were used with some success, but authorities still didn’t know for certain that all of the fish had been killed. A complete purge came finally when they poisoned the entire pond using a plant-derived toxin called Rotenone.

If not public awareness, the incident in Maryland at least spawned legislation. Within a few months, a federal law was passed banning the importation of snakeheads. But for many working on the problem, the ban didn’t go far enough. California is one of 13 states where it is illegal to import, transport, or even possess a snakehead. The state’s Fish and Game Commission has argued that the federal ban lacks teeth, as the high volumes of fish are imported together, and the snakeheads are small enough to hide behind larger ones. As Miles Young, a lieutenant in the California Department of Fish and Game, told the Sacramento Bee: “it’s been an enforcement problem.”

Back in Queens, now a full month since the finding of the five new snakeheads, the problem rages still. Undoubtedly, kin of the five exterminated fish are lurking underwater, devouring what’s left of the carp, white perch, and pumpkinseed fish native to Meadow Lake. Now closed for fishing, activity on the lake consists solely of local biologists setting traps for more snakeheads. But so far, they’ve had no luck.


On the Sandy Shoulders of Giants

In the spring of 1960, the largest of all recorded earthquakes rocked an idyllic seascape on the coast of Chile. Hundreds of locals, so frightened by the violent shaking of the land, sought refuge in small boats. They thought they were safe—until the sea roared with the 75-foot waves of the quake’s sister tsunami. All boats were lost.

Now, four decades later, a team of international seismologists have finally examined the stratigraphic tracks of the Chilean Giant and the devastating tsunami it caused. As revealed in last week’s Nature, their analysis of the layers of earth in the coastal region has shed light upon the long-misunderstood history of the 1960 monster.

Typically, the magnitude of an earthquake is directly related to the number of years since the last one in the area. So considering its enormity, at least 350 years should have elapsed between the Chilean quake and its immediate predecessor. And sure enough, Spanish conquistadors wrote of a large quake in 1575. But here’s the big mystery: other documents suggest the 1575 quake wasn’t the last one before 1960. Two others are documented: one in 1737 and another in 1837. This left those who were studying the 1960 event scratching their heads to figure out how so much energy could have built up in just 123 years.

The 1960 quake was caused when one piece of the earth’s crust—a tectonic plate—slid beneath another. Bordering the Chilean coast, the Nazca plate pushed under the South American plate to its east. Though it moved just three inches per year, over several centuries great amounts of energy built up, until May 22, when the earth finally succumbed to the pressure. And just fifteen minutes after the resulting quake—much like the ripples a dropped stone makes on the surface of a pond—the tectonic grind created a tsunami whose waves would reach as far as Japan.

Chilean eyewitnesses in 1960 said that even five miles inland, the tsunami coated the land with sand. Seismologists Marco Cisternas and Brian F. Atwater took advantage of this fact to clear up the contradictory historical evidence of the region’s earthquake timeline. As revealed in the Nature study, they dug up the earth’s settled layers of rock and sand. They assumed each layer of sand a footprint of a past tsunami, and thus a reliable indicator of a past earthquake. In this way, the team was able to piece together a 2,000-year record of seismic history. The results: the quake of 1575 appeared clearly in the stratigraphic record, while those of 1737 and 1837 did not.

So what about the documents of the latter two? The team suggests neither quake caused lasting ecological damage. After counting the trunk rings of 15 standing dead trees—presumed to have died in 1960—they found ten were alive in 1837 and two in 1737. The forest damage from the earlier quakes, then, could not have been as extensive as the havoc wreaked in 1960.

But this isn’t any too reassuring for those living on a fault line. The two smaller quakes, whose occurrences could not have been predicted based on the big one preceding them, were still devastating enough to go down in history—in ink, at least, if not in sand.


Another Poem from Meagan, the Birthday Girl

She Doesn't Wear a Jacket

Drugs lace their lingo.
Sex swims on their lips.
Smoke coats their convo;
She laughs at darted quips.

Crack bridges barriers
And booze opens doors.
Powder pushes pulses;
Inhibition hits the floor.

Inhibition is the jacket
That she rarely ever wears.
It doesn’t let her move enough.
Its color doesn’t dare.

And it’s autumn in the city,
Her steps are rushing-free.
She doesn’t don that jacket.
She’s asked: how can this be?

"My drug is in the sun’s shot.
My sex is in the grass.
That fog that coats my memory
Too shimmers on lake-glass."

You ask her if she’s crazy.
You query of her joy.
You seek to sweet-corrupt her.
You’re carved of natural boy.

She answers you with wind-words
Racing on the breeze...
She answers you with eyes-wide:
“I love life. This is me.”


Hey, Obese Americans: Sumo Wrestlers Say Eat Your Heart Out.

Like 60 million other Americans and a quarter of a million other Hawaiians, Fiamalu Penitani is obese. Severely so, in fact, with 520 pounds saddling a six-foot-four-inch frame. Fat all his life—in his Oahu high school, he was a 290-pound Greco-Roman wrestler and a nose guard for the football team—his girth quite literally gets in the way of many activities that smaller bodies take for granted. Flying is especially uncomfortable, for instance, because even spanning three seats, his back and hips get numb. Unlike the majority of other fat Americans, though, recent studies suggest there is little chance Penitani’s heart will ever succumb to disease or malfunction. He probably won’t die before his slimmer friends, either. So just what is it about this fat guy that gives him an edge in the fight against obesity-related health woes? Penitani—called Musashimaru in his professional life—was a grand champion sumo wrestler.  

In Japan—the land of painstakingly-pruned bonsai trees; where raw, lean fish prevails as the finest delicacy; where a popular hobby is the folding of paper squares into intricate birds and flowers; where the splendor of a geisha dance depends as much on the silks of her kimono as the lightness of her steps—the 1500-year-old, part-sport, part-religious ritual of sumo wrestling weighs in as the ultimate of cultural contradictions.  The Japanese are, by and (un)large, a lean people—the average man is 5’6” and just 143 pounds—and sumos, well, are not.

The rituals of a sumo match, too, are anything but dainty. Technically, a match is the one-on-one combat of two men, each trying to force the other to touch the ground or step outside an elevated clay ring. But as the typical brawl only lasts about 30 seconds, the charade that precedes it is the more fascinating element of the sport. The two loinclothed opponents start with elaborate gestures meant to intimidate each other. They slap their thighs, lift, flaunt and stomp the ox-like muscles in each of their tree-trunk legs, glare, groan, and even throw pillars of salt at their rival.  And though over 70 distinct moves—some so acrobatic they require the nimbleness of a ballerina—are officially recognized by the Japanese Sumo Association, the top wrestlers use only two or three of the most basic. Musashimaru’s favorite, for instance, was the brute strength maneuver oshi-dashi: a frontal push to drive the opponent backward and out of the ring.

Japanese sumo training begins as early as age 15, when the boy (and only boys, for the Shinto tradition purports that women and their “impure” menstrual cycles would contaminate the sumo ring) moves into one of 54 “stable houses” to train under a prominent master.  For the next few years in this spartan setting, the young hopefuls learn complex rituals and endure extreme physical training. Eric Gasper, an American who trained as a young wrestler in the early nineties, described the experience—where students may sleep 20 to a room, share squat toilets, and do their own cooking and cleaning—as “boot camp, prison, and war…all at the same time.”  On a typical day, the students wake at 4:30 a.m. and immediately begin a four-hour session of strength training.

Because there are no weight classes in sumo, the largest wrestlers have a major competitive advantage. But with such intense exercise, how do they put on so much weight? They eat—a lot. After the morning workout, wrestlers feast on chanko-nabe, a protein-rich meal-in-a-pot. There are dozens of variations of this hearty stew; typical ingredients include any combination of miso, beef broth, tofu, white rice, noodles, fish, pork, chicken, fried eggs, and fried root vegetables. And of course, the athletes wash down the enormous quantities of nabe with comparable amounts of beer and saki. But the real secret to weight gain comes right after the meal. Musashimaru, when once asked how he grew from 290 to 520 pounds, explained that sumos sleep immediately after eating, to insure slow digestion of their food and maximum retention of muscle mass.

A recent study from the Annals of Internal Medicine suggests yet another key element in the relationship between the sumos’ eating and sleeping schedules: hormones. Scientists have long known that the hormones ghrelin and leptin influence appetite; ghrelin secretion in the gastrointestinal tract stimulates appetite, while leptin production in fat cells represses it. But just last year, researchers at the University of Chicago published a further connection between these chemicals and the sleep cycle. The experiment subjected 12 healthy men to two days of sleep deprivation followed by two days of extended sleep, all the while monitoring their hormone levels, appetite, and activity. When sleep was restricted, ghrelin levels increased, leptin levels decreased, and consequently, the men’s appetites went through the roof. Their cravings for high-calorie foods increased by 45%. This hormonal play could thus explain the insatiable appetites of sumos—who get just six hours of sleep over the course of a typical day.

In November 2003, Musashimaru retired after a brilliant sumo career. In just 14 years, he became the first sumo wrestler in history to win 55 consecutive tournaments, and the second American fighter to achieve the most coveted rank of yokosuna, or grand champion.

Perhaps the only thing more surprising than Musashimaru’s rapid climb to the top of the sumo rankings is that his heart’s still ticking. For most obese people, their excessive weight, retained over months and years, steadily weakens their heart muscle. This makes obesity a major risk factor for all kinds of cardiovascular problems, including high blood pressure and fatal heart attacks. But for reasons just beginning to be understood by cardiologists all over the world, the hearts of sumo wrestlers are largely immune to these ailments.

Sumo wrestlers are physiologically different from the average obese Joe in two ways. First, their weight is made of mostly muscle instead of fat. Musashimaru’s body fat percentage at his heaviest, for instance, was around 20%. Compare that to the typical 500-pound man with a 70” waist (if, indeed, one can fathom a “typical” man of this enormity), whose body fat is about 35% of his weight.

Sumos also differ from other obese people in the way their hearts can handle the extra strain from their weight. Though the giants are some of the largest men in the world, the shape and function of their hearts is indistinguishable from those of the leanest of athletes.

Professional athletes are frequently diagnosed with a medical condition known as athletic heart syndrome. Characterized by an abnormally stretched heart muscle, the condition is basically the body’s way of adapting to strenuous physical activity. For a bigger heart means that a larger amount of blood (called stroke volume) can be pumped, and thus oxygen can be delivered faster to strained muscles and organs throughout the body.  But it seems that the phenomenon is not limited to lean athletes. A 2003 study published in the American Journal of Cardiology measured the heart size of 331 Japanese professional sumo wrestlers and found that just over 85% exhibited the ventricle dimensions of an athletic heart. This was surprising to the researchers, because the “static,” or non-cardio exercise done by sumos was not previously thought to strengthen the heart as much as that of, say, a marathon runner.

After the press conference where he announced his retirement, Musashimaru was quoted in multiple international newspapers mostly for just one phrase: “sumo hurts.” But apparently the pressure, harassment, and physical training required for excellence in the sport bring supersized health payoffs. And as anyone who has sampled it will tell you—tourists, internationally-acclaimed food critics, and especially the wrestlers themselves—chanko-nabe is delicious.