Gene blues

  • 14/10/1994

Gene blues Picture a scenario where a physician examines the genes of a foetus and tells the expectant mother that her child may turn out to be a psychopath/addict/schizophrenic/mentally retarded. The woman has 2 options: get the foetus aborted, or approach the gene boffs to cut and splice the DNA and give the foetus a new identity.

This sounds like scarifying science fiction, the stuff of Aldous Huxley or Philip K Dick or a host of cyberpunks. A decade ago, it would have been horror-show baloney; a decade later, it could well be as simple as getting your tonsils removed.

The message that genetics can explain, predict and even modify human behaviour is promulgated not just on sensationalist, half-baked talk shows but also by eminent, sober scientists. James D Watson, co-discoverer of the double helix structure of the deoxyribonucleic acid (DNA) molecule and the former head of the Human Genome Project that is mapping the entire human genetic endowment, said recently, "We used to think that our fate was in our stars. Now we know, in large part, that our fate is in our genes."

Descartes" axiom -- "I think, therefore I am" -- is passe. A group of post-modern scientists poised on the cutting edge of genetic study have another slogan -- "I inherit, therefore I am."

For all purposes, this could be the nihilism fighting which gave the world its major religions -- all of which exist on the basis that there is more to human life than mere fleshly matter. Many behavioural geneticists now boldly declare that the nature/nurture debate -- whether innate biology or external influences direct the course of a human life -- is as good as over. They also vehemently argue that genetic research may lead to the elimination of society"s most refractory problems, including drug abuse and violent crime. By pinpointing a gene, or genes, that may eventually trigger a particular disorder, scientists believe that they can develop gene therapies to cure the aberrations.

Some psychiatrists believe that fairly common disorders like schizophrenia and manic depression -- and even alcohol and drug addiction -- can also be traced to genes. The genetic link to human behaviour, they contend, will lead not only to better diagnosis and treatment of these disorders but also to more compassion towards sufferers and their families. Homosexuals, for obvious reasons in the vanguard of watchkeeping on genetic research, hold that society may become more tolerant of them if sexual orientation is shown to be a matter of unalterable biology and not free choice.

The mapping of the human genome has given a new lease of life to behavioural genetics, which had an infamous beginning in the sadistic Aryan eugenics that Hitler had kick-started (See box). Eugenics/genetics spent 4 decades lying out in the cold; but over the past 10 years, gene hunters have been more benign: they have unmasked the genes behind such crippling diseases as cystic fibrosis, muscular dystrophy and, last year, Huntington"s disease.
The Minnesota connection It was tough making the gene-behaviour connection in the first place. The most famous investigation into the connection is the University of Minnesota"s study on identical twins. Initiated in the late "70s by psychologist Thomas J Bouchard Jr, the study examined more than 50 pairs of identical twins who were separated shortly after birth and raised in different circumstances. Any differences between identical twins, who have an identical set of genes, were assumed to have been caused by the environment.

The group used a yardstick called "heritability" to measure the contribution of genes to a given trait -- say, eye colour, which stems entirely from genes, was defined as 100 per cent heritable. Height was 90 per cent heritable: meaning that 90 per cent of variations in height was ordered by genes and 10 per cent by diet and other environmental factors.

Bouchard"s team claims that practically all the traits it examined were partly genetically determined. Whereas most earlier studies had reported a 50 per cent chance of a child inheriting its parent"s intelligence, the Minnesota group claims that it is 70 per cent. The team further claims that genes may have a bearing on a person"s religiosity, political orientation, job satisfaction, hobbies, and even proneness to divorce.

Farfetched? The researchers buttressed their statistical findings with anecdotes about "remarkable" parallels between reunited twins. One case involved Oskar, raised as a Nazi in the former Czechoslovakia, and Jack, raised as a Jew in Trinidad. Both were reportedly wearing shirts with epaulettes when they were united by the Minnesota group in 1979. Both flushed the toilet before as well as after using it and enjoyed deliberately sneezing to startle people in elevators. Trait links
But when it came to pinpointing the genes contributing to a trait, the Minnesota study ground to a halt. To unearth this information, scientists in the early "80s developed techniques that exploited the fact that certain DNA fragments, called polymorphisms, are passed on from parents to offspring in a predictable manner. If a DNA stretch is consistently inherited together with a given trait -- blue eyes, for example -- geneticists inferred that the DNA either lies near a gene for that trait or is a gene itself. A polymorphism that merely lies near a gene is called a marker.

Behavioural geneticists basically work with 2 techniques -- linkage studies and association studies. In the former, investigators search for DNA stretches inherited in tandem with a trait running in the family. In 1993, researchers adopted this method to find a marker linked to Huntington"s disease, a crippling brain disorder that usually strikes carriers in middle age and kills them within 10 years. Since then, the same technique has helped nail down genes for cystic fibrosis and muscular dystrophy, among other diseases.

In association studies, researchers compare the frequency of polymorphisms in 2 unrelated populations, one with a specific trait and the other lacking it.

In 1991, Shelley D Smith of the Boys Town National Institute for Communications Disorders in Children, in Omaha, and David W Fulker of the University of Colorado, identified polymorphisms associated with dyslexia in a linkage study of 19 families prone to the reading disorder.

Robert Plomin, a psychologist at the University of Pennsylvania, is searching for "intelligence genes". He is studying 64 12-13-year-old schoolchildren, divided into 3 groups of those who scored about 130, 100 and 80 in IQ tests. He has uncovered several markers that seem to occur more often in children with the highest IQ.

Critics, however, argue that intelligence tests are poor indicators of success in business, the arts or even advanced academic programmes. Plomin thinks that a large number of genes may contribute to intelligence, and that at best he can only find a gene that accounts for a tiny variation in intelligence.

Brain disorders
Over the past few decades, studies of twins, families, and adoptees have convinced most investigators that the roots of schizophrenia and manic depression lie not in the mind or in society, as R D Laing would have it, but in the victim"s biological make-up. The problem now is one of incontrovertible verification, never an easy job in the empirical world of science.

In any case, in 1987, a group led by Janice A Egeland of the University of Miami School of Medicine claimed to have linked a polymorphism on chromosome 11 to manic depression in an Old Order Amish family. The same year, a team led by Miron Baron of Columbia University linked a marker on the X chromosome to manic depression in 3 Amish families.

But in 1989, a more extensive analysis of the Amish by a group from the National Institute of Mental Health ruled out any link between chromosome 11 and manic depression. And last year, Baron"s team retracted its claim of linkage with the X chromosome after a fresh examination of Israeli families with more sophisticated markers and more extensive diagnoses.

The study of schizophrenia is a step away from the real world. In 1988, a group headed by Hugh M D Gurling of the University College, London, reported in the British journal Nature a linkage between genetic markers on chromosome 5 and schizophrenia in Icelandic and British families. In the same issue, however, researchers led by Kenneth K Kidd of Yale University said that they failed to find any such linkage in a Swedish family.

In fact, all available evidence suggests that schizophrenia and manic depression are caused by the combined effect of several genes and environmental influences. Finding such a multiplicity of genes with linkage analysis may not be impossible, says Neil Risch, a geneticist at Yale University, but it will be considerably more difficult than identifying genes that have a one-to-one correspondence to a trait.

Tippler genes
The evidence for a genetic basis for alcoholism is even more tentative than for mental illness. Gurling found a decade ago that identical twins have strikingly contrasting drinking patterns.

In 1990, however, a group led by Kenneth Blum of the University of Texas Health Science Center at San Antonio claimed it had discovered a genetic marker for alcoholism. They claimed that the marker, called A1 allele, was associated with the D2 gene which codes for a receptor for dopamine, a neurotransmitter -- a chemical that helps transmit a nerve impulse. Blum"s work was followed by 3 more studies offering evidence in favour of a genetic basis for alcoholism.

The same year, however, Risch and Joel Gelernter of Yale University and David Goldman of the National Institute on Alcohol Abuse and Alcoholism reviewed all gene-alcoholism studies and found that only Blum"s work showed an association between the D2 receptor and alcoholism.

Gelernter and his colleagues point out that association studies are prone to debatable results. They suggest that the positive findings of Blum and his colleagues may have derived from a failure to account for ethnic variation. The limited surveys done so far have shown that the incidence of the A1 allele varies wildly in different ethnic groups, ranging from 10 per cent in certain Jewish families to about 50 per cent in the Japanese.

Crime in the blood
To American preoccupations, however, alcoholism plays second fiddle to a far more endemic problem: crime. Crime has become the most controversial area of behavioural genetics research. Its proponents argue that genetics research might yield methods for identifying and defusing potential criminals -- particularly those prone to violence -- at an early age.

In October last year, a Dutch-American team led by Han Brunner of the Nijmegen University Hospital reported linking a "syndrome of borderline mental retardation and abnormal behaviour," including "arson, attempted rape and exhibitionism", to an apparently rare mutation of a gene on the X chromosome. The gene codes for the activity of monoamine oxidase A (MAOA), a compound that metabolises neurotransmitters dopamine, serotonin, and noradrenalin.

In its mutated form, the gene doesn"t work, and the affected individual lacks MAOA -- which to the researchers suggested a relation between the gene and aggressive behaviour. Again, however, the finding hasn"t been replicated. Critics lambast genetic investigations into crime. These studies, they say, inevitably suggest that blacks are predisposed to crime, given that blacks in the US are 6 times more likely than whites to be arrested for violent crime. Says Peter Breggin, director of the Center for the study of Psychiatry in Bethesda, Maryland, "Behavioural genetics is the same old stuff in new clothes. It"s another way for a violent, racist society to say people"s problems are their own fault, because they carry bad genes."

The importance of being gay
The ostensible purpose of investigations into mental illness, alcoholism and crime is to reduce their incidence through preventive care and genetic therapy. But scientists studying homosexuality have a different goal: simply to test whether homosexuality is innate, as many homosexuals believe, or a matter of free choice.

In 1991, Simon LeVay of the Salk Institute for Biological Studies in San Diego lent credence to the genetic basis of alternate sexuality. LeVay, who is gay, focused on a tiny structure in the hypothalamus, a region of the brain known to control sexual response. He measured this structure, called the interstitial nucleus, in 19 homosexual men, 16 heterosexual men and 6 heterosexual women. He found that this structure was almost twice as large in heterosexual men as in homosexual men or heterosexual women. He postulated that the interstitial nucleus "is large in individuals oriented towards women", whether male or female.

Critics, however, question LeVay"s conclusion that homosexuality is biological simply because the brains of male homosexuals resemble the brains of women. That assumption, they say, rests on yet another assumption: that there are significant anatomic differences between heterosexual male and female brains. But to date, there have been no replicable studies showing such sexual disparity.

LeVay"s findings are nowhere genetic. But various other researchers have tried to establish that homosexuality is also genetic. In December 1991, J Michael Bailey of Northeastern University in Boston and Richard C Pillard of Boston University announced they had uncovered evidence of the genetic basis of homosexuality in humans. They studied 161 gay men, each of who had at least one identical or fraternal twin or adopted brother. The researchers determined that 52 per cent of the identical twins were homosexual, as compared to 22 per cent of the fraternal twins and 11 per cent of the adopted twins. Bailey and Pillard derived similar results in a study of lesbians.

And, last July, Dean Hamer and his group at the National Cancer Institute reported that homosexuality may be associated with a region at the tip of the long arm of the X chromosome known as Xq28. Because each mother passes on to her male offspring just 1 of her 2 X chromosomes, the probability that 2 sons will receive the same Xq28 is 50 per cent. Hamer"s group looked at 40 pairs of gay brothers and found that 33 -- 83 per cent -- had identical Xq28 markers.

Hamer"s findings, like many others, are yet to be replicated. But even if they are, they are unlikely to mollify the critics of previous efforts to link specific genes to human behaviour. The critics" complaints about the previous work fall under 4 heads: misuse of statistical methods; failure to define the trait under study; bias in the selection of cases and controls; and inadequate sample sizes.

Even the most careful work can be undone by an inadequate sample size. Much of behavioural genetics research has attempted to link traits to single genes that are passed on in a simple Mendelian manner from generation to generation. The model is the single gene on chromosome 4 that causes Huntington"s disease, which was identified by looking for genetic markers in a Venezuelan family with the world"s highest incidence of this dreadful condition.

Unfortunately, this attractive model is misleading as far as behavioural genetics is concerned, according to Brian K Suarez, a psychiatrist at the Washington University School of Medicine in St Louis. "We knew sickle-cell anaemia and Huntington"s were monogenic for decades before we discovered which genes were affected," he says. "I don"t believe that any of the psychiatric disorders are that simple. They probably involve multiple genes, which may interact in diverse ways. As a result, confirming a discovery requires a sample large enough to capture its vacillating effects."

Animal models
In recent years, based on experiments on animals, researchers have developed some remarkable methods for identifying the contributions of groups of genes to behaviour.

Seymour Benzer"s group at the California Institute of Technology has identified several genes that are important for the normal functioning of the nervous system in the fruitfly, Drosophila melanogaster. One example is the gene named shaker, mutations in which cause flies to quiver violently under anaesthesia.

But genes such as shaker raise the issue of how to prove that a particular gene is involved in determining behaviour, which is controlled by the nervous system. A shaker-like mutation, which changes the nervous system"s function, will obviously affect behaviour. But does it qualify for categorisation as a behaviour gene? Those who say no argue that mutations in these genes don"t alter a specific behaviour: they just make the fly sick.

A gene that qualifies as a behaviour gene and which was identified in Benzer"s lab is called period (per), which controls the fruitfly"s 24 hour daily rhythm, including sleeping, feeding and mating patterns. Removing the per gene can lead to curious behavioural changes. For example, males with the per mutation serenade with an altered rhythm. Stranger still, laboratory manipulation of per can change the courtship song cycle in a predictable way. Replacing part of the per gene can cause the male to sing with a shorter rhythm.

These findings show that per is a gene whose variations produce subtle behavioural differences that when acted upon by natural selection -- nature"s way of perpetuating traits that make for a fitter species -- may ultimately result in a new species. Indeed, it has been found that the per gene in species inhabiting northern and southern Europe differs slightly.

In the case of per, success came from finding a gene and discovering its role. Other researchers are looking at behaviour first and then trying to trace the gene responsible.

Marla Sokolowski of York University in Toronto, for example, observed 2 forms of feeding behaviour in the larvae of wild fruitflies. The larvae she dubbed "rovers" moved around continually on their food; others called "sitters" remained in one spot to savour their meal. Sokolowski suspected that there may be a single gene behind the 2 behaviours.

She was right. Most of the differences between the strains could be explained by variation in a gene she named foraging (for). Like per, the for gene is subject to natural selection, even in the lab. Crowded conditions favour rovers, apparently because they range farther in search for food; sparsely populated situations favour sitters, which conserve energy by staying put.

But despite her findings, Sokolowski doesn"t believe that genes are solely responsible for behaviour -- in animals or in humans. If, for example, a rover larva is deprived of food before being given a chance to feed, it will probably behave like a sitter. "We have to get away from genetic determinism -- that the genes determine our behaviour independent of the environment."

Because insects such as fruitflies are far removed from humans on the evolutionary scale, researchers are turning to mammals such as rats and mice. Those working on mice have received a big boost from a technique for making "knockout mice", in which specific genes can be inactivated to study their effect.

Researchers in Strasbourg, France, have knocked out the gene for one type of receptor for serotonin, a neurotransmitter. The resulting mice display aggressive behaviour toward other mice. Because humans have a similar kind of serotonin, Hen believes that the receptor may be responsible for aggressive behaviour in humans. Boozing rats
Ting Kai Li of Indiana University has bred 4 rat strains, 2 of which prefer a slightly alcoholic solution to ordinary water and 2 of which shun alcohol. The tippling rodents find alcohol reinforcing for its drug effects, not just as a thirst quencher, says Li, as shown by the fact that they will continually press a bar not only to get a drink of water spiked with alcohol, but even to get alcohol injected into their brains or stomachs.

Li"s group has shown that these lushes have low levels of serotonin and dopamine. Drugs such as Prozac, which enhance serotonin"s effects, diminish the rats" craving for booze. Prozac doesn"t block alcohol craving in all imbibing rats, however. A strain bred in Finland doesn"t show the serotonin defect -- and doesn"t respond to Prozac either. That suggests there may be variation in the human condition as well.

Some human alcoholics may have a serotonin deficiency and respond to Prozac, he argues; others may not. These contrasting rat strains show the influence genes can have on complex behaviour. Until recently, however, there was little hope of actually locating the multiple genes that govern the craving for alcohol. Now, thanks to new genetic techniques for analysing complex traits, several groups are starting to sniff clues; other behavioural geneticists are exploiting the new techniques to find genes for behaviour other than imbibing.

One such researcher is Jeanne Wehner of the Institute for Behavioural Genetics in Boulder, Colorado, who is searching for genes involved in spatial learning in mice. Wehner has been studying 2 common lab strains of mice that differ dramatically in their ability to learn and remember the location of a submerged platform in a tank of water. Mice in one strain are good learners; those in the other are not.

She found that the slow learners had lower levels of an enzyme called protein kinase C (PKC) than the gifted ones. But that didn"t mean that PKC had anything to do with learning; it might have been a coincidence that the enzyme varied between the 2 strains.

To find out whether the enzyme really does influence the ability of the mice to learn, Wehner turned to one of the popular new genetic tools: recombinant inbred (RI) mice, so called because they are inbred strains formed by recombining or mixing the genes from the 2 commonly used lab strains. Each RI strain has a unique mix of genes from the 2 parent mouse strains from which it is formed.

Wehner chose a collection of RI strains with random assortments of genes from the 2 strains of mice and found a significant correlation between the activity of PKC in the brain and performance. And that finding suggests that the PKC gene is one of the many genes that influence spatial learning.

But Wehner is cautious. She says that it is better to be safe than sorry in this field. "Learning is very difficult to study because of both genetic and environmental influences." Even after researchers manage to find a gene or a group of genes that shape behaviour, they may still be a long way from knowing precisely how those genes exert influence.

Twilight zone
Behavioural genetics is clearly stumbling through a twilight zone. Mounting evidence from animal and human studies shows that genetics has a role to play in human behaviour, although scientists are still struggling to find the genes responsible for that role.

As researchers grope for more successful methods, different groups continue to dispute the societal implications of their findings. For every geneticist who fears that "neurogenetic determinism" will erode human dignity, there are other researchers who believe these discoveries may help individuals with mental and physical problems.

Xandra O Breakefield, a member of the Dutch-American team that linked the mutation in the gene for MAOA to aggressive behaviour points out that MAOA deficiency has many effects, including the inability to metabolise wine, cheese, and many types of Chinese foods -- a severe reaction that can lead to cardiac failure. "With many of these deficiencies, if you don"t change the diet within the first year, it"s too late. Doesn"t that mean we should look for this problem early, instead of mulling over ethical implications?"

Says Gelernter,"There is definitely a genetic basis for many conditions, ranging from Tourette"s syndrome to alcoholism. We just want to try to get what the mechanisms are."

Tourette"s syndrome is a highly heritable disorder that causes its victims to move and speak uncontrollably. A boy who had Tourette"s kept grabbing himself in the crotch publicly. The school authorities turned him in, and the father was accused of child abuse. The family broke apart. Had the family known that the syndrome was heritable and treatable, it might have stayed together.

Critics, however, contend that behavioural genetics is still mired in the same problems that have always plagued it. Behavioural traits are fiendishly difficult to define, and practically every claim of a genetic basis can also be explained as an environmental effect.

Even if researchers are able to identify genes for various disorders, argue critics, the possible dangers outweigh any benefits. The best that researchers can hope for is to find, say, a gene associated with a slightly elevated risk of schizophrenia. Such information is more likely to lead to discrimination by insurance companies and employers than to therapeutics benefits, they say.

History corroborates this fear. In the "70s, insurance companies began requiring black customers to take tests for sickle-cell anaemia, a genetic disease that primarily affects blacks. Those who refused to take the test or who tested positive were denied coverage.

While bitter passions will continue to rage over this controversial science, there is a growing understanding that the interaction of genes and environment is much more complicated than the simple "violence genes" or "intelligence genes" touted in the popular press. It appears that the age-old nature-nurture debate may eventually end in a tie.

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