Neurosciences Offer Researchers Diverse Opportunities

if (n == null) The Scientist 13[18]:26, Sep. 13, 1999 Profession Neurosciences Offer Researchers Diverse Opportunities By James Kling Great promise for advances in neuroscience existed at the beginning of the Decade of the Brain. Like most life science disciplines, neuroscience had benefited from huge strides in molecular biology, and many expected neuromuscular diseases such as multiple sclerosis and Parkinson's disease to be vanquished quickly. Not surprisingly, public anticipation has gone unfulfilled as this decade winds down. Neuroscience has made great progress, but most of its therapeutic application is still years away. Chris Fibiger Even if public expectations remain unmet, neuroscience has only scratched the surface of the brain. Technical advances and discoveries have led to new and deeper questions concerning neuroscience and neurological disorders. Because neurological diseases, including Alzheimer's, Parkinson's, multiple sclerosis, and psychological disorders, are so costly--and because the aging U.S. population is becoming more susceptible to such disorders--government and industry are funneling research money into neurological research. And that means jobs. It also means lots of interesting scientific questions. "The brain is the last great bastion in biology. We understand so little about the brain today, and there's still so much fascinating information that we are waiting to get access to, that [neurology] will be an unbelievably exciting career," says Chris Fibiger, vice president of neuroscience discovery and clinical investigation at Eli Lilly & Co., Indianapolis, Ind. Neuroscience encompasses the study of brain function as well as the mechanisms that govern the peripheral nervous system. Thus, there are two broad categories of disease targets: neurodegenerative diseases such as Parkinson's and multiple sclerosis and psychological disorders including depression and schizophrenia. "And these are [converging] in that research is beginning to show that they are both driven by the same basic brain mechanisms," says Mark S. Kramer, senior director in clinical neuroscience at Merck & Co., Whitehouse Station, N.J. During this decade, researchers have developed a variety of new drugs to treat both disorder types--the most famous of which is Prozac, a selective serotonin reuptake inhibitor produced and marketed by Eli Lilly. Companies have also come out with drugs to treat Alzheimer's disease, Parkinson's disease, and schizophrenia, but all of those drugs were developed based on drug screening and clinical observation rather than an understanding of the underlying neural mechanisms. By the mid-1980s, several key advances in the understanding of the nervous system began to drive new approaches. Nerve cells transmit a signal when one cell releases a store of neurotransmitter and the next cell in the chain receives it, activating a membrane signal pathway that in turn generates an electrical signal. Until the 1980s, researchers believed there were only nine small-molecule neurotransmitters, but advances in molecular biology and biochemistry yielded another 50 neuropeptides during that decade. More recently, researchers have discovered that the neurotransmitter receptors on the surface of the nerve cells have more permutations than was once thought. In fact, there are large families of those receptors and many different subclasses. Further knowledge of those subclasses may allow researchers to tease apart the neurological effects of drugs, according to Robert McBurney, chief scientific officer at Cambridge NeuroScience Inc., Cambridge, Mass. "Everyone knows you can make a sodium channel blocker to make pain go away, but unfortunately those drugs are anesthetics, not analgesics, so they make all sensation go away. The key is to find a sodium channel blocker that has more importance in the pain pathway than in the [general physical sensation] pathway." In addition to finessing neurotransmitters and their receptors, there is now hope that future therapies could involve regeneration of lost nerve cells. Until very recently, most researchers assumed that after the completion of brain development, human beings were left with a finite number of brain cells that get slowly whittled away over the remainder of their lifetimes. But new evidence suggests that nerve cells of the brain, just like most other kinds of body cells, can be regenerated under the influence of the right growth factors. Some researchers began to dream about finding neural growth factors that could replace brain cells lost to a stroke, for example, or the continuous attack of Alzheimer's. "Before about 1995, there was one growth factor [known to have an] influence on the nervous system--today, I can't even count the number of new proteins that direct the fate of nerve cells," says McBurney. Those discoveries prompted a lot of excitement and several clinical trials to treat neurodegenerative diseases, but none proved successful. The trials probably failed in part because of the blood brain barrier, which is a natural membrane that acts as a biological filter to prevent large particles such as proteins or pathogens from entering the brain from the bloodstream. The frustrations of protein therapeutics are nothing new. But those discoveries have led to other questions that are sure to keep neuroscientists busy for a long time to come. Every protein has a cellular receptor, and if researchers can identify the cellular pathways that lead to neural regeneration, they may be able to design small-molecule drugs capable of being delivered to the brain, according to McBurney. Unlike they do for many other disease targets, companies often do not devote drug discovery programs to the creation of therapies for a specific disease. Instead, companies such as Merck assign researchers to work out the mechanisms of neuronal pathways. "Although we don't have a dedicated program in schizophrenia, we are constantly evaluating mechanisms that influence schizophrenia, and if we came up with one [that suggests a therapeutic intervention], we would immediately move into that target area," says Scott A. Reines, vice president of clinical research at Merck. Such mechanism-based approaches make neuroscience one of the most diverse fields in the life sciences. Researchers enter neuroscience from all sorts of backgrounds, with specialties including neurobiology, electrophysiology, neurochemistry, biochemistry, behavioral pharmacology, and neuropharmacology, to name just a few. Companies emphasize the importance of a broad-based knowledge. "It's important that these subdisciplines know enough about other subdisciplines, so they can have meaningful communication," explains Fibiger. "Many people who call themselves neuroscientists started out life doing something training in one or another area, and then taking their background and experience and applying it to the study of the nervous system," says Dennis Choi, professor of neurology at Washington University in St. Louis and president-elect of the Society for Neuroscience. Scientists from nearly all subdisciplines are in demand, although molecular biologists are "a dime a dozen because the system is producing huge numbers of Ph.D. students with molecular biology training .... That's where a huge proportion of [National Institutes of Health] funding is going these days," maintains Fibiger. That emphasis on molecular biology has been a great boon to neuroscience, but it has also created an imbalance. "Behavioral pharmacology has gone out of fashion," says Reines. Many academic research programs focus so much on gene expression and molecular studies that they have de-emphasized the whole animal. "We look at behavior and then receptor occupancy in the brain as that animal is behaving. We need people who can carry out those experiments." Fibiger agrees: "There's still a tremendous need in industry for people qualified to do that kind of work. The brain is the organ of behavior, and we have to ultimately test our compounds in behaving animals. Without that behavioral endpoint, we are in great difficulty, and we are absolutely experiencing difficulty in recruiting sufficient numbers of well-trained behavioral pharmacologists." The inter-connectedness of nerve signals is also leading to a high demand for systems biologists. "If you want to know how audition [hearing] works, you need to know how cells and synapses work. But all of that information wouldn't give you a clue about how the process works. [You have to uncover] the paths that create the auditory system, then start working at how the individual parts interact; what kinds of processing occur, what steps we go through in order to recognize sound," says Choi. For more information Society for Neuroscience www.sfn.org Just like the human nervous system, neuroscience is an interconnected web of subdisciplines strung together to form a complex scientific endeavor. The brain is still a black box, and the field will no doubt be tackling fundamental questions well into the future. Aside from the scientific challenge, Fibiger sites one more reason to enter the field: "Neuroscience deals with the issues that are the most important to every human being, and that's the mind, [and] conscious experience." For many, that's motivation enough. James Kling (Web address: nasw.org/users/jkling) is a freelance science writer in Bellingham, Wash.

Neurosciences Offer Researchers Diverse Opportunities

Neurosciences Offer Researchers Diverse Opportunities

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