Researchers studying the brain have traded dramatics for genetic finesse.

Two generations ago, researchers in the budding field of behavioral neuroscience were taking out brain areas wholesale and carefully recording what went amiss with their animal subjects. Cats with carved out amygdalae tended to turn nasty, attacking their handlers, as well as whatever was placed in front of them. Mice with discrete lesions placed in tiny regions near the base of the brain would execute heroic leaps and dash around the lab in a frenzy if someone cracked open their cages.

Scientists then, with this sketchy information, would try to posit what crucial brain regions governed which behaviors. Aside from observations of humans with stroke or head trauma, its all they had to go on.

Today, neuroscience is much more refined. A knockout mouse lacking only the molecules of a single gene can be similarly observed, but the affected biochemistry can be minutely detailed. Revolutionary inroads into the genetic basis of biology have made cloning the aim in nearly all biological disciplines, even in the study of behavior.

But, despite increasing genetic knowledge, doctors still lack the clinical means to adequately treat most major conditions of the nervous system. The Neurogenetic Institute now under construction at the University of Southern California Keck School of Medicine aims to change this. The nascent institute, funded by a whopping $110 million commitment from the W.M. Keck Foundation, celebrated groundbreaking for its new research building in September. A major recruitment effort is already underway to stock the slated labs with new faculty.

W. French Anderson, one of the founders of gene therapy and a faculty member at the University of Southern California (USC), says that the Keck neuroscience initiative has "a vision similar to the Hubble telescope." What the university "now has to do is pull it off, get the quality of people" who can do it. "Our job is to get the right people" to join an already jazzed set of young as well as established USC neuroscientists, Anderson says. "I feel we should get superstars."

One investigator already working at USC is Jean Shih, professor of molecular pharmacology, who lately has been seeking the genetic basis of aggression. Like many puzzles of human behavior, the problem of aggression has been attributed to the signal molecule, serotonin, the target of the popular drug Prozac. Perhaps the trends of neuroscience follow the ability of scientists to measure things, and serotonin is certainly measurable these days. For example, two decades ago, the number of docking sites on nerve cells that scientists knew received the message of serotonin was two; this has burgeoned to 15 today.

But Shih was working on the earlier discovered enzymes that sweep the spent transmitter from the synaptic gap between neurons once the message is delivered. Then she decided to go ahead and clone the enzymes' genes; a modern twist, she says, to clear up an old controversy: was the different ability to handle different neurotransmitters due to different variants of the same enzyme, and at what level did the difference get introduced? Not just a conundrum, but a key to developing more specific treatments with less side effects, for such conditions as Parkinson's disease and depression.

"We started cloning the gene, and then we also got the whole genomic structure" of what turns out to be two genes coding for two separate versions of the enzyme. The very slight difference in the two gene sequences, says Shih, "shows us that the [two enzymes] originally came from the same ancestral gene." Interesting biology, and interesting clues to how to target new therapeutics. But an accidental discovery along the way has also led to new insight into aggressive human behavior.

One long known human pedigree, in which many male members of a Dutch family suffer from dramatically aggressive behavior, is now understandable in genetic terms. The enzyme monoamine oxidase (MAO) was suspect, as a psychiatrist had found serotonin deficits on urinalysis - a measure that a psychiatrist would tend to make, as urinary metabolites of neurotransmitters are used to follow action of the classic psychiatric drugs. Indeed, one base pair in the MAO A gene is missing in the men. A modern lab construct, knockout mice lacking the gene for MAO A , also shows unusual aggression. For those mice lacking the means to produce the B enzyme, aggressive behavior doesn't appear.

It's a clear-cut case of the chemical basis for behavior. "With the MAO A knockout mice in hand, we have an animal model" for aggressive human behavior, Shih says. Fifteen different molecular docking sites have now been cloned that respond to serotonin, "so we're trying to see which receptor mediates the aggressive behavior."

Just the kind of example, Keck investigators would say, of the spotlight genetics can cast on the ill understood nether world of complex brain processes. The requirement, they agree, is to first understand the molecular basis of the brain's biology. "My focus is actually to understand the basic process of signaling, the signal molecules responsible for vision," says assistant professor of opthamology Jeannie Chen, who earned a Ph.D. in 1990 and has been working on the very basic biochemistry going on in back of the eye, at USC's Doheny Eye Institute. Two generations ago, pioneering researchers in the field of visual perception would blindfold cats or turn frogs' eyes upside down and chart the alterations in sight and behavior. Chen can manipulate a mouse's photoreceptor genes. "We start to play around with these molecules and mutate them . . . to create an animal model for diseases."

"What we don't know right now is how disruption in the basic signaling causes a cell to kill itself," says Chen. "The cell death is ultimately what is responsible for blindness. As long as we have an animal model, we have a means of studying that."

Research has already gathered the epidemiologic data to allow scientists to begin to ferret out the genes responsible for types of blindness or glaucoma, Chen says. "The potential is there," to have the Institute uncover such genes.

With regard to finding the genes responsible for such disorders as schizophrenia, Cheryl Craft states that "we're no closer than we were seven years ago. It's just not a simple task." Craft is chair of cell and neurobiology at USC, a basic neurobiologist who has crossed over to study the genetics of the brain. The need is to recruit "really top-notch neurogeneticists, mathematicians, and computational biologists," says Craft, people who can help answer these questions. The newborn Institute intends to convince 35 new investigators to join within the next 5 years.

An epidemiologic database that may provide leads to possible gene candidates for neurologic disorders is actually already available at USC, which is what swayed the Keck Foundation to fund the university, says professor of preventive medicine Brian Henderson, who formed the USC/Norris Comprehensive Cancer Center and is now director of the Neurogenetic Institute. The state of neuroscience endeavor is "very much like the cancer field was - we knew very little, we didn't know what the relevant characters were in the pathways of cancer development and that's where we are today in the brain." When it comes to candidate genes in the brain, for instance, which might be involved in addiction or schizophrenia, "it hasn't been very successful so far because people are working fairly blindly," Henderson says. Yet from the large population based studies that USC has conducted for cancer, he says, "we can look across different ethnic groups and occurrence of these diseases and get clues to causation."

The records amassed at USC amount to a database on a million people, some followed for 20 years, with records on nutrition and other environmental influences included. Chen says that the Keck people trust that Henderson will be able to pull off a successful search for candidate neurologic genes.

"What we thought was an environmental issue" for cancer has been changed by the data amassed by the epidemiology, Henderson claims. "It's clear now these are genetic" differences that cause cancer to crop up more frequently, say, breast cancer in native Hawaiians, or prostate cancer in African Americans, findings that came from the epidemiologic data amassed at USC.

Henderson says he knows what is needed to solve the obviously complicated genetics of Alzheimer's or other degenerative diseases of the nervous system, "I think it's this intangible, but very real thing in science, as in most walks of life, [with] the casual encounters over a cup of coffee in a hallway where you make a connection that you otherwise won't make . . . you magnify your ability to get things done." He saw it happen at the cancer center.

In the past decade, Henderson says, cancer rates have fallen, for the first time in half a century. With the same approach, he says, science can take on "the last great hurdle," diseases of the brain. "The drug companies are waiting for this to happen," Henderson adds, as once the genes involved are known, "you can target drugs to that defect, a drug that's for [that person's] kind of depression, or [another's] type of schizophrenia."

Shih already knows that just the forebrain in a mouse can be targeted, and this area driving the emotion of aggression can be steered via serotonin. In collaboration with a group in France, she finds that ketanserin, a drug that blocks one type of serotonin receptor, also blocks aggression in mice. With transgenic, knockout mice and the gene for the MAO enzyme hooked to a promoter that specifically works only in the forebrain, "we generate a new line of mice [and] these mice don't have MAO in all of the body and brain except for the forebrain where we put MAO back," says Shih, "and these mice do not fight." "This experiment nicely demonstrates that the serotonin in the forebrain is responsible for aggression."

"This is the state of the art," says Shih. "It's a very exciting time for research. While many socioeconomic reasons give rise to human aggression, she says, and "the cases we are studying are a very drastic change, they are totally deficient. Maybe a decrease in MAO also will have some effect on aggression" and animals with such changes could serve as a template for drug design, says Shih, "these are the future studies." Stress management is important, and fetal development may be changed by the excess of serotonin due to the defect in MAO. "All this gives us a number of ideas on the possible cause of aggression in humans."