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© The News and Observer, 2000

 

Out of Obscurity

by Jon Franklin

        Though basic research is fundamental to modern medicine, the connection is complex and often indirect. Most laboratory biologists spend their working lives confined to the labyrinths of their own arcane scientific subcultures, speaking their own separate languages and having little or no direct contact with practicing physicians. And so when Anthony LaMantia got the invitation to speak to a convention of psychiatrists his first reaction was puzzlement.

        Why were a bunch of shrinks interested in his thoughts about the chemical mediation of the development of the forebrain in mice?

        "But I thought about it," he recalls with a grin, "and, you know, it was Hawaii. this was December. And I thought, 'Why not.'"

        Thus begins a tale that proceeds along the vague frontier between biology and psychology, ranging from the creation of art to the creation of consciousness itself and providing, in the end, a glimpse into the incoherent agony of schizophrenia. Along the way it also captures the role of chance and human personality in understanding human disease.

        It was not a story LaMantia himself would have believed, as a young man. For one thing, as a young man he had no use for science. His interest was in the creative life, which to him meant art and, especially, music. Science was anti-art - dry, calculated, devoid of the human spark, and he avoided it whenever he could.

        All the same, his parents wanted him to be a doctor and it is difficult to be a doctor without taking a science course or two along the way. He signed up for a six-year MD program at the University of Chicago in 1979, figuring he'd grit his teeth and somehow struggle through.

        But along the way he found himself liking what he had previously despised. Many years later he would realize that until then he had simply never had good teachers. But all he knew at the time was that, suddenly, the science of life wasn't dull at all. It was hauntingly beautiful. Sometimes, there was even something symphonic about it. As he descended deeper and deeper into the mechanism of the thing called "life," he eventually became fascinated by the mysterious grace with which a single cell became a fetus.

        The cell divided and divided again, forming a hollow ball. In time the ball developed a crease - and as the crease deepened, the ball elongated, becoming a three-layered trough. This was all orchestrated by a chemical conductor of some sort, and the cells performed with graceful obedience.

        Under whatever influences, the edges of the trough grew, curling upward and outward before finally arcing inward again, meeting, and fusing into a three-layered tube - the first movement of the composition called life. That tube was the forerunner of the body; the outer layer would become the skin, the middle layer would become the muscles, bones and organs. But LaMantia's interest was inexorably drawn to the inner layer, properly called the neural tube, and the bulb that would form on one end and become, many cell divisions later, the brain.

        It wasn't long before LaMantia knew he didn't want to become a doctor. He wanted to do something more creative. He would be a scientist!

        As LaMantia came into science, researchers were just documenting how the growth of the fetus was choreographed by certain chemicals. The chemicals carried messages in their shapes; they entered the fetal cells, made their way to the DNA, and switched some genes on and other genes off. Which chemical messenger entered each cell was in large part a matter of proximity and position . . . but whatever the trigger, it was such messenger chemicals that determined the ultimate destiny of each fetal cell, whether it would be muscle, bone, kidney, skin . . . or brain.

        Thus, for example, a chemical called retinoic acid was known to coax out the protuberances that would form arms and legs. Later in life that chemical would function as vitamin A - and serve a totally different purpose - but in the beginning it was the conductor of the quartet of limbs.

        In 1988, as a graduate student, he went to work with neurobiologist Dale Purves, at Washington University in St. Louis. One of Purves' mentors, Viktor Hamburger, a famous embryologist who had discovered the growth factors that modulated the shaping of the spinal cord.

        Though now retired and in his 80s, Hamburger came in once a week for a brown-bag lunch with Purves and his students. LaMantia was fascinated by the courtly old scientist, and what his generation had done.

        Hamburger's discoveries, along with those of others, had eventually led to the discovery of a long list of compounds that shaped the deep structures in the brain - substances that scientists like LaMantia would come to know, familiarly, by such names as "noggin," "chordin" and "sonic hedgehog."

        These chemicals were produced by tissues in the middle level of the fetus and turned genes in the neural tube on and off. This coaxed out the cells of the midbrain and hindbrain much like retinoic acid did for the limbs.

        "They told one patch of cells to do one thing and the other patch to do something else," LaMantia would remember, many years later. "There's this whole series of tissue-to-tissue interactions that tells the spinal cord and the hind brain where it's going to be, what's the bottom and what's the top and what kind of nerve cells to make at each location."

        But those known processes, LaMantia discovered to his fascination, did not extend to the sculpting of the forebrain. No one knew how that was built. In other words, those parts of the brain that produced intelligence and emotion were formed of totally different processes from those that shaped the deeper brain structures.

        "We knew vaguely that there had to be molecular signals that were doing this job," LaMantia recalled, "but no one knew what they were. And we knew there had to be downstream genes that were turned on and off by these molecular signals, but we didn't know what they were, either. And so I thought about it and thought about it, and I came to understand that, wow! This was the coolest problem that was available in neurobiology."

        So it was that understanding the creation of the forebrain, the most highly organized chunk of matter in the known universe, became LaMantia's quest.

        Of all the possible chemical switches that might come into play, LaMantia thought retinoic acid was the most likely. It was known to be a switch in other parts of the body and, besides, it was known that if it was given in excess to a mother just before the fetal tube fused, the resulting brain would be defective. Most obviously the olfactory bulb, where animals process smell and humans process smell and at least some emotion, would fail to form.

        Life passes quickly for a young scientist. Purves moved from Washington University to Duke, and LaMantia came with him. Graduate school was followed by post-doc work with Purves, in which LaMantia spent years mapping the developing brains of monkeys. But as he earned his credentials he was also cranking up his research on developmental neurochemistry, working in collaboration with a molecular biologist at Duke, Elwood Linney. In 1998, his apprenticeship finished, LaMantia moved to UNC and set up his own laboratory but he continued the collaboration with Linney.

        There, still working with Linney at Duke, LaMantia would travel to the very frontiers of experimental biology. Mice were impregnated and their fetuses removed and dissected, their component parts to be subjected to different chemicals. At one point cells were genetically engineered to turn blue when exposed to retinoic acid; those cells were cultured and plated out, then pieces of the fetal heads of mice were laid upon them to see where, if anywhere, retinoic acid was being produced.

        Over time, as the experiments were altered and repeated, again and again, a pattern began to emerge. LaMantia's guess had been correct. A population of cells in the middle layer of the fetal tube, near the end where the brain was forming, were indeed producing retinoic acid.

        The acid that seeped inward turned on the genes that formed the olfactory bulb; that which seeped in the other direction, toward what would be the inner skin of the nose, turned on the cells that would, upon maturation, compose the nerve circuitry of the nose.

        It was all very neat and beautiful, LaMantia thought.

        "It makes beautiful sense. The part of the brain that's going to cope with the information and the part of the nose that's going to detect the information develop from the same signal. They both get this signal from the [middle layer of fetal tissue] that says, 'start building the olfactory part of the forebrain' and 'start building the odor-detecting nerves in the nose.'"

        More work showed that if that choreography was somehow disrupted, then that part of the neural tube didn't develop properly. The result was mice which had no olfactory lobe and, therefore, were unable to smell.

        There were other malformations as well - malformations that might have rang a bell. Mice given excess retinoic acid also had the kind of dramatic defects associated with the failure of the tube to close properly. That included cleft palate, hair lip, and abnormalities of the jaw and aortic arch.

        The process of science dictates that the work is not done until the paper is published, over the years LaMantia produced a series of papers detailing how the mammalian brain was sculpted. But it was a 1997 paper in The Journal of Comparative Neurology with the improbable title of "Disruption of Local retinoid regulated gene expression accompanies abnormal development in the mammalian olfactory pathway" that got him the invitation to Hawaii.

        There the gathered psychiatrists listened, spellbound, as the UNC scientist described his smell-blind mice. Afterwards, he found himself seated at a big table in a sushi restaurant surrounded by the heads of psychiatry from a laundry list of important universities. He remembers asking himself, "What am I doing here?"

        Did he know, they asked him, that pregnant women who received too much or too little vitamin A early in their pregnancies often gave birth to children with dramatic defects . . . and that, in one study, those children had a high risk of developing schizophrenia 18 or 20 years into their lives.

        As a matter of fact, LaMantia said . . . no. It was news to him. Nor had he thought much about schizophrenia, and certainly not in connection with his work.

        In the days that followed the UNC scientist got an education in schizophrenic psychopathology and various observations that connected it to vitamin A. He learned, for example, that during World War II a population in Holland was deprived of vitamin A - and, two decades later, many of the children gestated during that period developed schizophrenia.

        And then, much later, an acne cream with high levels of vitamin A went on the market in the United States and was later linked to serious birth defects in women who had used it in early stages of pregnancy. Those defects included hair lip, cleft palate, and abnormalities of the jaw and aortic arch - precisely the problems seen in mice whose gestational retinoic acid was disrupted.

        LaMantia, working in his obscure corner of basic science, pursuing his own curiosity and the beauty of neural choregraphy, had run full tilt into what was probably the most important issue in psychopathology. He had brought the psychiatrist's disparate observation together, made it all make sense.

        Vitamin A, so important for the health of the skin and the eyes in post-fetal life, had other uses in the early stages of gestation - and among those uses was the sculpting of the forebrain.

        Given good general health, the mother could manufacture enough of the chemical to do the job. But if she was starved of essential nutrients, as happened in Holland during the Second World War, she lost that ability . . . and the child's brain in the vicinity of the olfactory lobe might not develop properly. The result, twenty years later, might be schizophrenia.

        If the expectant mother was given too much vitamin A, as happened with the acne skin cream, then the excess flooded the fetus and confused the system - with a similar result. The forebrain would be malformed, the olfactory lobe would be shrunken or absent, and the baby would have a high risk of schizophrenia.

        That was not necessarily the lone cause of schizophrenia. Trauma, for example, was known to cause it. But retinoic acid imbalances might be a key to many, and perhaps even most, instances of the disease. One way or the other, LaMantia's work explained more than any other scientist ever had.

        As LaMantia and other scientists looked at the biochemistry, it seemed to them that the safety margin might not be very great. It wasn't long before experts were cautioning pregnant women against taking any vitamin A at all, without first talking to their doctors. LaMantia himself, though no physician, worried in print that a pregnant woman might even overdose on natural sources of vitamin A, such as liver, milk, or egg yolks.

        Meanwhile, as the story got out, LaMantia heard more and more confirming anecdotes. Schizophrenics, he learned, have more than their share of cleft palates, hair lips and aortic arch malformations. And then, recently HOW RECENTLY, he got a call from a psychiatrist who, after reading LaMantia's work on the olfactory lobe, had decided to test some schizophrenics' ability to smell.

        "And if you can believe this," says LaMantia, "out of a group of ten schizophrenics they're all anosmic! None of them can smell. And these researchers followed up with MRI scans, and the patients turn out to have very small or no olfactory lobes."

        But in the past year, as excitement built in the clinical world, that LaMantia started, inexplicably, to get just a little bored. It was important work, true. It might lead - one could always hope - to ways to prevent and treat the disease. Given the disruptive nature of schizophrenia, that could have dramatic long term effects on health costs and social stability. And yet, and yet . . .

        "It was fun for a while," the scientist remembers. "It was exciting. It was unusual, because so few basic scientists get to see their work being applied directly to human illness, and . . . yes, it was real thrill. But then, eventually, you realize it's time to get back to the lab, and to the other problems that are waiting for you. I'm not a doctor, you know. I'm a scientist, and I . . .

        He pauses, looks at the ceiling, smiles to himself.

         

        "Science, to me, is a creative endeavor. Oh, sure, there's a lot of hard, repetitive work and I've done that, too. But in the end it's a creative, as creative as music or any other art.

        "In my own business, which is the cell biology and molecular biology of how you put the forebrain together, we have certain tools. We have a way of studying this in the laboratory. We have a way of asking what particular genes might be active and how they might be modulated. We also have the tools of mouse molecular biology . . . I'm hoping we can take the twenty or so [pertinent] genes and sort out what they're doing in early development, as far as the forebrain goes. This is my work.

        "I hope what I do will be useful. Any basic scientist does. But the practice of medicine, clinical medicine . . . that's someone else's business, not mine. It's not something that I can do, and I don't understand it well enough to even make any speculations.

        "What I'm good at, what basic science is good at, is using the tools of molecular biology in creative ways. Creative. That's the heart of it, applying the tools in creative ways, in the effort to determine how nature goes about making a brain. You have to assume that that will be useful to someone, and you have to be excited when it is"

        But my business is the laboratory. And this has all been fun, really fun. But it's time to get back to the thing I do best. And, you know . . . it's sort of a relief."

Jon Franklin
jonfranklin@nasw.org