Building Neuropharmacology

By Jason Socrates Bardi

In a 1991 address to the Association of Neuroscience Departments and Programs, Professor Floyd Bloom, who is chair of the Department of Neuropharmacology at The Scripps Research Institute (TSRI), remarked, "Maintaining the highest possible level of talented researchers relies critically on the ability to recruit, train, and retain the best young students to the neurosciences."

And if that address voiced Bloom's commitment to the next generation of neuroscientists, his work as chairman of the Department of Neuropharmacology embodies it. Since its founding in 1989, the department has grown steadily in both size and stature. It now occupies over 60,000 square feet of laboratory space in several of the buildings across campus and has nearly 300 employees—faculty, students, post-docs, and staff. The department is currently one of the world's leading centers for research aimed at understanding the interaction of such factors as viruses, drugs, or chemicals upon neuronal activity.

"I don't have to set the pace—we have a lot of distinguished senior investigators, younger people, and newly arriving [scientists] who are expanding the department," says Bloom.

What Bloom does do is to encourage an entrepreneurial spirit among the department's investigators to turn basic discoveries, particularly those that are involved with the human genome, into biotechnological products—tools and drugs that will have a positive effect on human health.

"The idea is to make a discovery that is useful and turn it into a diagnostic or an application or a way of life that will keep you healthy," he says. "The medications of the future, in my view, will be medications that keep you on the healthy side before you happen to get symptoms because it's harder to get rid of things once they've started."

A Prescribed Course

While it is not quite accurate to say that Bloom was born into medicine, it is fair to say that he was born around medicine. In Minnesota, where Bloom grew up, his father ran a pharmacy. As a boy, Bloom spent many hours working for his father—running deliveries, doing chores, and working the register.

Later, his father would play a pivotal role in his decision to attend medical school at Washington University. "For my father, being a doctor was the highest calling you could have—it meant independence of mind and independence of choice," recalls Bloom. "He wanted me to be a physician."

While in medical school, Bloom studied membrane biophysics and neuropharmacology along the way to what he thought would be a career in internal medicine and the pharmacology of hypertension. But he never made it out of the laboratory. In his early career, he focused on the brain monoamine systems (which includes norepinephrine, dopamine and serotonin), characterizing their cellular actions, mapping out their synaptic sites, determining their post-natal development, and looking at the functional properties of the systems in attention, sleep, and waking behaviors. Later, he spent several years devoted to comparable studies on neuropeptides, cellular functional data, and mapping data for the opioid peptides—somatostatin, vasoactive intestinal polypeptide, and neuropeptide Y.

He was drawn to neuroscience as a way to address some of the most pressing conditions, like schizophrenia, depression, drug abuse, and alcoholism. "There weren't many medications that were prescribed when I was growing up that were useful for mental illness," he recalls. "Sedatives were about the best we had."

Today, good therapeutics are available to treat several of these conditions, but there is a great need for more.

Antidepressants, for instance, make up one of the largest markets in the United States, netting billions of dollars in annual sales. However, one out of every ten Americans suffers from some form of major depression. And there is still a great need for a fast-acting antidepressant (normal antidepressants take two or three weeks to take effect). This is problematic because the core symptom of serious depression is suicidal tendencies. In 1997, for instance, 30,535 Americans committed suicide, making it the eighth leading cause of death in the United States that year.

Alcoholism continues to be a major problem in the United States as well. The direct and indirect public health costs of alcoholism are estimated to be in the hundreds of billions of dollars yearly. More than half a million Americans die each year from smoking-related illnesses. And more than three quarters of a million people in this country have AIDS, which can have deleterious effects on the brain.

One of the problems with developing drugs to treat many neurological conditions is the incredible difficulty of doing basic research on the brain. In a 1991 lecture to the American College of Neuropsychopharmacology (Bloom was president of this body from 1988 to 1990), Bloom pointed to a 1990 study that had found that basic, preclinical research seemed to contribute less to the development of psychiatric drugs than to anesthetic or cardiovascular drugs.

Bloom remarked in his lecture that this was probably due to the fact that basic science lacks good animal models for many psychiatric conditions, which would allow scientists to study the details of normal and pathological brain states in vivo.

Under Bloom's leadership, TSRI's Department of Neuropharmacology has spent a considerable amount of time and effort developing animal models of addiction, alcoholism, and viral pathogenesis, amongst others, and a number of neuropharmacology investigators are working to develop further models of major psychiatric conditions.

In addition to leading TSRI's Department of Neuropharmacology, Bloom is currently serving as the president of the American Association for the Advancement of Science (AAAS), a position he moved into after working for several years as editor-in-chief of Science, the flagship publication of the AAAS. As his last duty in that position, he will open the AAAS annual meeting and give the president's lecture in February 2003.

Somebody who doesn't know Bloom could assume that today, after a distinguished career that has taken him from Yale to the National Institutes of Mental Heath to The Salk Institute and finally to TSRI 20 years ago, he might be at a place in his career where he would be mostly looking back.

He's not.

In fact, Bloom is looking forward to the truly great challenges that await neuroscientists in the 21st century. For much is yet to be discovered about the brain.

"The brain uses well over half of the genome," says Bloom. By most recent estimates, there are around 40,000 genes in the human genome, which means that the brain uses about 20,000 genes. "If you look for brain-specific molecules in all the books [in the library], you won't find 2,000," Bloom says. "That's how much further we have to go."

Identifying the Genes that Predispose

"The real trick now," says Bloom, "is to figure out the genetic vulnerability factors for the major illnesses that we don't have effective ways to treat—such as schizophrenia, depression, drug abuse, and alcoholism."

There is no question that having particular genes predisposes you to certain conditions and there are probably other factors that can turn a vulnerability into a susceptibility. For instance, if your identical twin has bipolar disorder, your chances of having the disorder as well may be 100-fold higher than any average person on the street. There are very strong genetic susceptibility factors, but the question is, what are they?

"That's where [neuroscientists] are at now—the discovery of many of the genes we didn't even know existed and how they are affected in the genomes of people with diagnosed mental illness," says Bloom.

Part of the problem may be that many mental illnesses, like bipolar disorder, are multifactorial—they result from a combination of several interacting factors from genes and the environment.

The story, of course, does not stop with the identification of genes. Basic science can go on to describe the expression, regulation, and localization of these genes—both in "normal" and in pathological states—and relate these microscopic observations to macroscopic effects, such as behaviors and mental conditions.

Bloom, in fact, pioneered the microscopy of neurons and neurotransmitters decades ago in order to complete molecular descriptions of neuronal function. In order to figure out which neurotransmitters were important for which neurological processes, he had to figure out where they were in the brain and to develop methods that allowed him to see these neurotransmitters with light microscopes and through electron microscopy. Once he accomplished this, he was able to see the synapses that had the chemicals of interest and thus identify, categorize, map, and perturb genes essential for important functions in the brain.

Bloom also pioneered the use of molecular biology in neuroscience. In the 1980s Bloom, in collaboration with Professor J. Gregor Sutcliffe of TSRI's Department of Molecular Biology, used recombinant DNA technology to identify unknown gene products expressed selectively in the brain—by isolating thousands of mRNAs from brain tissue and cloning and sequencing the ones that were not detectable in the liver or kidney.

Bloom now is devoted to devising systems of computer-assisted tools to collect, collate, organize and analyze the multidimensional data sets that characterize modern neuroscience research. He focuses much of his time at TSRI on maintaining a laboratory that specializes in quantitative microscopy—observations of neurons and neurotransmitters with light microscopes. The laboratory is funded as part of the large Interacademic Neuroscience Consortium Center Grant, which is sponsored by the NIH and led by his colleague George Koob.

"My laboratory is largely a core function for members of the department and other collaborators," says Bloom.

This work grew out of the TSRI Alcohol Research Center, of which Bloom was administrative leader in the early 1990s. The center pioneered the use of animal models to analyze human drug self-administration and later expanded to involve all of the disciplines of the neurosciences, with the department's faculty developing similar models for psychostimulants (amphetamine and cocaine) and for opiates (morphine, heroin).

The Story of the Brain

The story of the brain is not just one of tissues and cells, but of bodies and behaviors—encompassing everything from the identification of genes relevant to the brain and basic questions of their regulation and function to the broadest measures of how these genes affect behavior. It covers everything from the development of neurons in the embryo to the degeneration of neurons in old age; from the expression of genes to the expression of behavior; and from mechanism to treatment of diseases.

Bloom once described the field of neurosciences as including "virtually any activity that contributes to an understanding of the biological basis of mental activity, regardless of species, in health or disease." Interdisciplinary approaches naturally lend themselves to such a broad field, and collaboration has always been the norm in the neurosciences. Today, it is becoming a necessity.

Where once the story a neuroscientist told would take the reader from cells to circuits to function, now the same neuroscientist must weave a more elaborate tale: from genes to proteins to chemicals to cells to neurons to circuits to function to behavior in complex eukaryotic—indeed, human—life.

"It requires that you combine anatomy, chemistry, physiology, pharmacology, behavioral science," says Bloom, "and now, molecular biology and computer science."

With this more extensive set of disciplines grows not only the number of observations that may be relevant for a particular story, but the number of specialists who need to be involved to tell it well.

"Virtually everybody in the department is collaborating with someone else in the department," he says.

And that is exactly where he likes the department to be.



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"I don't have to set the pace-we have a lot of distinguished senior investigators, younger people, and newly arriving [scientists] who are expanding the department," says Professor Floyd Bloom, chair of TSRI's Department of Neuropharmacology. Photo by Mark Datsrup.