"My aggression gene made me do it" could become a plausible not-guilty plea, judging by knockout mice deprived of monoamineoxidase synthesis.

Those ferocious rodents came into existence by a sort of serendipity,at the Institut Curie in Orsay, France. Virologist Edward De Maeyer,a director of research at the Institut, told BioWorld Today how ithappened:

"These transgenic mice are part of an approach we have pursued forthe past seven years, developing gene therapy against HIV, usingconstitutive [i.e., needing no inducer] production of interferon. Weintroduced an INF-beta gene to make them more resistant to viralinfection.

"Our experiment," De Maeyer continued, "was done to answer thefollowing question: Can one live with a constitutively expressedinterferon?"

Out of three strains that his laboratory transfected, "we obtained onestrain of mice that displayed abnormal, aggressive behavior. Themales had bite wounds all over their body, whereas normal micedon't have such wounds, and don't fight. The Monoamine Oxidase A[MAOA] deleted rodents had greatly elevated levels of serotonin andnorepinephrine.

"We are not interested in aggression," De Maeyer explained. "We arevirologists, not neurologists. But we needed a definite answer to thefollowing question: Is the fact that these mice fight more, and haveaggressive behavior, due to their constitutive synthesis of interferon?If so, of course, this would compromise our gene-therapy project. Oris it due to something else?"

Did The Interferon Do It?

A full account of the problem, and its clarification, appears in thecurrent issue of Science, dated June 23, titled: "Aggressive behaviorand altered amounts of brain serotonin and norepinephrine in micelacking MAOA."

Norepinephrine is one of the "fight-flight-fornicate" hormonespumped out by the adrenal glands to help mammals confront dangeror stress. (See BioWorld Today, April 17, p. 1.) Serotonin is aneurotransmitter much implicated in aggressive animal behavior.Once these potent molecules enter a synapse on their way to work,MAOA enzymes kick in to mop up the excess.

The MAOA gene resides on the X chromosome. So does the gene forinterferon-beta. "Transgenes very often get integrated into othergenes," De Maeyer observed, "and knock them out. So withoutknowing it, by pure chance or coincidence, we got knockout mice forthe MAOA gene."

What about MAOA-minus humans?

The Science paper suggests that "The finding that MAOA-deficient[murine] males . . . display enhanced aggression . . . supports the ideathat the particularly aggressive behavior of the few known humanmales lacking MAOA is not fostered by an unusual geneticbackground or complex psychosocial stressors but is a more directconsequence of MAOA deficiency."

Those "few known human males" belong to an extended Dutchfamily. Their "abnormal behavior syndrome," reported in Science onOct. 22, 1993, ran the gamut from "impulsive aggressive outbursts,often in response to anger, fear or frustration" to arson, rape andexhibitionism.

Fibroblast skin cultures from these three men showed that they shareda point mutation in their MAOA structural gene, which completelyknocked out the enzyme's activity, thus allowing serotonin "and to alesser extent dopamine and noradrenaline" to build up in theirsynapses.

For reasons unknown, "MAOA activity in two carrier females wasnot different from that of a noncarrier female and two unrelatedcontrols."

Although the MAOA gene is on the X chromosome, De Maeyerdoesn't think "it has anything to do with sex. The X chromosome," heobserved, "is one of the largest, in mice and man, with a great manygenes that have nothing to do with sex [i.e. gender]."

De Maeyer sees no immediate application of his unanticipatedfinding, either for testing or treating human males. Butpsychopharmacologist John Kehne of the Marion Merrell DowResearch Institute in Cincinnati told BioWorld Today that the Frenchfinding is "an intriguing new approach. He added, "There's anextensive literature linking serotonin and aggression in animals, butI'm unaware of any other studies in humans."

Kehne, who reported on serotonergic activity last November to theNeuroscience meeting in Miami Beach, said that applying MAOAgene mutation to possible diagnosis or therapy for aggressive humanbehavior "is a reasonable expectation at this point." n

-- David N. Leff Science Editor

(c) 1997 American Health Consultants. All rights reserved.