Blood Matters Page 25

  Chapter 11

  Biobabble

  ANASTASIA KHARLAMOVA, a tall, pretty, and confident woman in her early forties, shed her urban-professional image by exchanging her sheepskin coat for a dirty lilac down number and slipping on a pair of hiking boots that had seen better days. She led me down a gravel path, through a gate, to a field filled with cages holding hundreds of silver foxes. We entered a covered aisle lined with two rows of female foxes. They barked and squealed and made funny quacking noises and banged their aluminum feeding boxes with their paws, trying to draw attention to themselves. Anastasia murmured Russian endearments as she walked along, occasionally stopping to take a fox out of a cage and cuddle her. One of the foxes resisted going back in, wriggling into Anastasia’s arms and angling to lick her face.

  A few aisles over, we were greeted by ominous silence—until Anastasia touched her fingers to the cage bars. Then the fox in the cage would bare her teeth and lunge at the front of the cage, closing her mouth with a metal snapping sound.

  “Careful of your nose,” said Anastasia, addressing a fox. “They have no teeth left by the end of their first year,” she explained, turning to me.

  The silver-fox farm outside of Novosibirsk is probably the longest-running continuous genetic experiment in the world. In the 1950s the Soviet geneticist Dmitry Konstantinovich Belyaev set out to figure out what happened to wolves on their way to becoming dogs. That is, how did wolves, which can be generally, but accurately, described as weighing between fifty and a hundred and thirty pounds, having a narrow chest and a powerful back, possessing a bulky coat that is gray to gray-brown in color, as well as stout and blocky muzzles and pointy perky ears, manage to turn into creatures that can weigh as little as two pounds or as much as a hundred and seventy; have a long stringy white coat or no coat at all; have a barrel chest or a ridge down a slender back; have a square jaw or ears that flop all the way to the ground? Granted, people bred dogs to look a certain way—but any breed had to start with a spontaneous mutation or mutations that changed the wolf’s coloring, coat, the degree of ear perkiness, or any of the other components of wolf morphology. Everything science knew about mutation rates said that this could not have happened in the mere twelve to fifteen thousand years that had passed since wolf started turning into dog.

  Belyaev was a lucky man: He was working with animals. It had been roughly a dozen years since the science of genetics had essentially been banned in the Soviet Union. Former geneticists were working as housekeepers and street cleaners. Belyaev managed to continue studying animal genetics under the guise of doing physiology research. In the late 1950s, as Soviet policies relaxed following the death of Joseph Stalin, Belyaev was tapped to head a new genetics institute, to be founded in Siberia. He gathered scattered geneticists from around the country—one of the women he picked to head a laboratory in the institute had worked as a preschool teacher until she was exposed as a geneticist and fired, eventually finding work playing piano in a restaurant—and set up the institute and the experiment of his dreams. He picked foxes because they were closely related to wolves and could be obtained in large numbers, from fur farms.

  Belyaev’s theory at the start of the experiment was that there was something about the process of domestication that threw genetics out of whack. “Dmitry Konstantinovich believed that behavior is regulated through a complex combination of regulatory molecules, including hormones, neurons, neuron receptors, hormonal receptors,” explained Lyudmila Trut, a geneticist whom Belyaev had drafted as a college senior half a century earlier and who took over the silver-fox experiment after Belyaev’s death in 1985. “And he believed that these complex interdependencies accounted for variations in behavior.” Trut, a very small woman wearing very large eyeglasses, had been teaching for more than four decades, and she spoke like a lecturer: slowly, clearly, and using complete sentences that she could drop upon being interrupted and then pick up again. “So that when animals were selected for behavior—let’s call it domesticated behavior—this actually led to changes in the regulatory mechanisms: the hormonal systems, the neuronal systems in the most general sense. And Dmitry Konstantinovich supposed that by changing the state of these regulatory molecules in the process of domestication, we changed the functional activity of a great many genes, causing the broadest spectrum of changes.”

  Dmitry Konstantinovich Belyaev turned out to be right. First, he proved that it is possible to breed for behavior—in other words, that behavioral traits are genetically determined. He began with a hundred female and thirty male foxes, whose reactions to humans were closely observed by researchers. Since the foxes came from a commercial fur farm, they had cleared the first hurdle on the path to domestication: They were capable of reproducing in captivity, and they were not afraid of humans. Fear, it could be said, had already been bred out of them. What differentiated the foxes from one another was their degree of friendliness toward humans.

  The Siberian researchers eventually developed a 9-point friendliness scale, where +4 denotes an animal that eagerly jumps out of the cage to be cuddled by a human, while a -4 aggressively lunges at a human even when the cage is closed. A 0 reflects an animal that exhibits neither aggression nor friendliness: It does not attack but does not allow itself to be handled either. Out of the first group of foxes, Belyaev selected a very small percentage of the females and an even smaller percentage of the males—those deemed the most tame—and bred them. Nine years and nine generations of foxes later, Belyaev was in possession of a small population of silver foxes that were unlike any silver fox that had gone before. They loved people. They loved to be given attention by people. They loved to be handled by people. They were, from all appearances, ready to leave their cages and go live with humans in their homes, becoming fully domesticated.

  The foxes stayed in their cages, though. The experiment was designed to limit human contact to avoid contaminating genetic influences with environmental ones. The farmworkers who fed the animals were not allowed to linger near the cages of friendly foxes. To ensure that workers maintained the same attitude while walking past the cages of tame and aggressive animals, the experimenters often mixed the animals, placing the friendly and unfriendly types in adjacent cages. There was no doubt: Animals could be bred for behavior, and dramatic changes in the behavior of a species took mere generations to achieve.

  Once they proved that they could domesticate the wolf’s nearest relative in nine generations flat, Belyaev’s researchers moved on to other animals. They took on minks, which seemed to present a challenge. Unlike the fox and the wolf, minks are not universalists: While the canines can live just about anywhere, minks have strict location requirements, setting up home only near water. In addition, unlike wolves and foxes, they are loners. So the idea that a mink could be bred to the point of being domestication-ready seemed dubious. Still, the experiment worked, once again proving that it is possible to breed animals for behavior, which proved that behavioral traits are genetically determined.

  Both the minks and the silver foxes were farm animals, accustomed to living in captivity and unafraid of people. Now the experiment had to be tried on wild animals. In the 1970s Belyaev’s people went on a rat hunt in the forests around Novosibirsk. They looked not for rats that lived in building basements but for the certifiably wild sort. Many of the captured rats died. Many others refused to reproduce. The rest—roughly two hundred, including the first generation born in captivity—went on to form another historic experiment. The researchers divided them, at random, into three groups. One group would be bred for domestication: Only the friendliest of the rats would be allowed to reproduce while the rest were killed. Another group would be bred for aggression: Only the meanest ones would be allowed to have babies. The third was a control group: A small number of randomly chosen rats would be allowed to reproduce in each generation, presumably producing offspring that were little different from their wild forebears. The control group fell victim to budget cuts around the time the Soviet Union coll
apsed, but the tame and aggressive groups lived on, the latter maintaining an average aggression score of -3.

  Irina Pliusnina, a small middle-aged woman with close-set eyes and a broad smile, led me into a large barn filled with a noxious smell. She handed me a scrubs-green robe and slippers to change into: If Anastasia had changed to keep her clothes clean when she handled the foxes, here the goal was to keep me from infecting the rats’ environment with anything I might have dragged in from the outside. She opened a cage and gently picked up a rat by putting her gloved hand around the rodent’s body.

  “Here, my little girl,” Pliusnina cooed. “Look, you could never handle a laboratory rat this way. They pick them up by the tail in labs. Our rats can’t stand to be handled by the tail. They like it only when they are handled like this.” She was basically embracing the rat. “What a good girl. She is one of those scary wild rats of Novosibirsk, you know, the stuff of legend for many years.” The rat stretched its head toward Pliusnina, as though reaching for a kiss. The researcher leaned down to her subject, gushing: “So you are my mean wild rat. Mean mean mean rat. Mean mean mean mean.”

  The real mean rats were in cages in the room next door. Pliusnina carefully chose a cage to open: All of the rats were either pregnant or nursing, which made them especially aggressive (the tame rats in the other room were also in various stages of motherhood, but this did not deter them from cuddling with Pliusnina and even letting her handle their tiny offspring). Finally, she opened a metal door. The rat stood on her hind legs, her front paws lifted as though ready to strike.

  “This one is a boxer,” said Pliusnina. “If I reach for her, she will attack.” This made her roughly a -3 on the tame-aggressive scale. “Quite a contrast, yes?” said Pliusnina. “That’s sixty-seven generations of selection.” Small change in evolution time, but further proof that breeding for behavior was possible, even in a population of animals caught in the wild.

  Pliusnina continued to sing the praises of domesticated rats. They were, she explained, basically much nicer creatures. They were calmer, more self-confident, less nervous, and more inclined to try new things than their aggressive cousins—better-adjusted all around, in other words. In an “open-field” test, where rats that are normally caged are placed in a relatively large round arena and videotaped, the tame rats showed themselves to be much calmer than the aggressive ones: They ran around less spastically, and they defecated less. In another test, the rats were placed in a shallow tub filled with milky water, so they could not see the bottom of the tub. Their goal was to swim to a small platform on which they could sit: Otherwise, the tub was just deep enough to force them to keep swimming. The top of the platform was obscured by the milky water, but its location remained stable. With four swims a day, it took the domesticated rats just one day to learn to find the platform, while the aggressive ones took five days.

  The tame rats reaped rewards for their tameness: They had more babies, and, like the tame foxes, they could have them more often than the aggressive group or than is normal in the wild. By the time the tame rats were in their thirteenth generation, tests showed that their pituitary-adrenal system had grown far less active in responding to emotional stress. By the twentieth generation, their basal levels of corticosterone, the rodents’ primary stress hormone, were consistently lower than normal. The Siberian geneticists were breeding happy, well-adjusted, and highly fertile rats.

  After a while, they got into breeding other kinds of rats as well: disturbed rats, cataplexic rats, and hypertensive rats. The last were laboratory chief Arkady Markel’s pet project. Markel was a soft-spoken bespectacled white-haired man who had a large office with a corner cordoned off to form a sort of cubicle, in which he sat, partly obscured by wooden partitions, staring calmly at his small flat-screen computer monitor. He wore a gray soft-knit cardigan. One got the feeling that if Arkady Markel were a rat, he would not do well on the open-field test. He would, on the other hand, be tame to the point of depression, and would certainly not be hypertensive. But, being human, Arkady Markel had great compassion for his hypertensive research subjects.

  Markel’s rats, bred for hypertension, turned out to share a very specific psychological profile. In unfamiliar surroundings, they tended to have a higher-than-average interest in exploring. But while they shared this trait with Pliusnina’s supertame rats, they were different on other scores: When they saw a stranger rat, for example, they expressed less fear and more aggression than might have been expected. They were, in other words, doers.

  “Strictly speaking,” explained Markel, “hypertension is not a disease but an aspect of an individual’s psychological makeup. Its purpose is to ensure an active state. Hypertension is the price of success.” Hypertension, in Markel’s opinion, is a classic example of a trait that provides a selective advantage. First, hypertension—at least the sort he studied—is genetic, though probably extremely complex, caused by a large set of genes, each of which might play only a small role in shaping the condition. Second, the condition affects an extraordinarily high percentage of the human population: more than a quarter of all adults in developed countries. Third, if the effects of hypertension were solely negative, the trait would have been washed out of the population, or at least watered down. But Markel argued that the condition goes hand in hand with modernity, enabling the individual energy output that competitive contemporary societies demand—which was how the condition grew more and more common.

  Markel had set out to breed rats that would have high reactive blood pressure—that is, their blood pressure would rise higher than other rats’ in response to stress. In order to measure the rats’ blood pressure, the researchers placed a tiny cuff on the animal’s tail, thereby fulfilling both requirements of the experiment: The cuff provided stress to the rat and measurements for the scientist. To measure a rat’s resting blood pressure, the researchers placed the creature in a jar saturated with enough ether to put the rat to sleep for about five minutes, which was enough time to place the cuff on its tail and take the measurements. It turned out that rats bred for high blood pressure under stress also had higher-than-average resting blood pressure. “Because all of life is stressful,” explained Markel plaintively.

  As responses to stress go, spiking blood pressure is perhaps the most constructive. In any case, it corresponds to our idea of the norm—unlike, say, going catatonic, which corresponds to our idea of mental illness. Markel and his colleagues created a line of rats that froze in response to stress, such as being scared or being pinched. Whatever gene predisposed rats to going catatonic, it was inherited in a dominant pattern—that is, if one parent was affected, half the offspring would be affected as well—which made it relatively easy to create a breed. They got a population of rats inclined to freezing in an uncomfortable vertical position, and proceeded to decapitate them and study their brains and blood. The catatonia-prone rats turned out to share a number of neurological and hormonal traits with human schizophrenics. At the same time, they also shared a number of traits with humans who are depressed: They had lower levels of certain hormones and neurotransmitters, and they had sleep patterns characteristic of depressives. They failed one of the standard ratdepression tests, though: They appeared to maintain their ability to enjoy sugar water, which may have meant they retained their ability to enjoy life generally. At the same time, they acted depressed in another common test: When they were placed in a tall glass jar partially filled with water, they gave up and started floating after only a short period of kicking their legs in a doomed attempt at escape. This, Markel’s researchers suggested, may have marked their cataplexic rats as suitable models for studying both schizophrenia and depression—making them a good first stop for testing new antidepressants and antipsychotic medication. At the same time, some other researchers at the institute were arguing that the quick-to-give-up rats were actually wiser rats, rational individuals who opted to save their energy. Pliusnina’s tame rats also tended to give up faster in the glass jar.

&
nbsp; “The problem with these tests is that we cannot ever tell what they are thinking,” said Nina Popova. “Did the animal go still because it has no fear or because it is paralyzed by fear?” Popova, who founded the Laboratory of Behavioral Neurogenomics in 1971, received me in her office about a block from Markel’s lab, in a dilapidated gray concrete building, the sort that had looked modern half a century earlier. The office was square, with glassed-in bookshelves of polished wood and a massive oak desk that took up most of the room. It looked like the study of a classics professor, someone who studied things so established they were virtually calcified. But Popova was studying something very new. She aimed to trace what she acknowledged was “the very long road from protein synthesis to behavior”—that is, she was trying to define the relationship between genes and the ways people, or at least mice, act.

  Popova’s lab had its own strain of cataplexic rodents: She and her staff studied mice. Her mice were quite like Markel’s rats: They froze upon being pinched and stayed that way. They also did not move around much in the “open field,” and they quickly gave up in the glass jar with water. Were they simply calm, rational, and well-adjusted? Unlikely. Just ten days on antidepressants turned them into normal-acting mice. Which may not have told the researchers much about what the mice were thinking, but it meant that the mice were good models for preliminary testing of new antidepressant medication.

  Popova’s lab had other weird mice, too. A group of French researchers had accidentally bred a line of mice with the monoamine oxidase A (MAOA) gene knocked out of them. The MAOA gene was probably the first so-called behavior gene on the map. In the early 1990s a Dutch geneticist identified a large family in which roughly half of the males suffered from mild mental retardation and made others suffer from their odd, often aggressive behavior. They engaged in arson, attempted rape, exhibitionism, and random impulsive violence. The condition was apparently hereditary, and, since it affected solely the males in the family, most likely linked to the X chromosome: The females in the family had two X chromosomes, one normal and one abnormal, and in half the cases they passed the abnormal one on to their offspring. The boys who got it would be affected; the girls would be healthy but could pass the gene on to their sons. In 1994 the Dutch researchers published their findings showing that the culprit was a badly damaged MAOA gene, which fast became known as “the aggression gene.” A couple of years later Han Brunner, the lead researcher on the project, published an article arguing that the moniker was inaccurate, if only because “genes are essentially simple and behavior is by definition complex.”