9

Sizing Up the Promise

How can neuroscience best fulfill its rich promise in the Decade of the Brain? One of the events of the symposium sponsored in July 1990 by the Institute of Medicine and the National Institute of Mental Health was a panel discussion that focused on the questions “What needs to be done?” and, more pragmatically, “What can be done?” Led by Joseph B. Martin, dean of the School of Medicine at the University of California, San Francisco, the panel consisted of half a dozen spokesmen from government, academia, industry, and the private sponsorship of research, all sectors committed to advancing neuroscience.

The question “What needs to be done?” calls up a vigorous response from the neuroscience community. The needs are great: with some form of brain illness or mental disorder likely to strike one in every eight Americans, and with as many as 1,000 different dysfunctions of the brain thought to be determined at least in part by genetic makeup, it is clear that this field of knowledge holds great potential to alleviate illness and suffering, through the clinical tools of diagnosis and treatment and through genetic analysis. The imperative to use our cur-



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DISCOVERING THE BRAIN 9 Sizing Up the Promise How can neuroscience best fulfill its rich promise in the Decade of the Brain? One of the events of the symposium sponsored in July 1990 by the Institute of Medicine and the National Institute of Mental Health was a panel discussion that focused on the questions “What needs to be done?” and, more pragmatically, “What can be done?” Led by Joseph B. Martin, dean of the School of Medicine at the University of California, San Francisco, the panel consisted of half a dozen spokesmen from government, academia, industry, and the private sponsorship of research, all sectors committed to advancing neuroscience. The question “What needs to be done?” calls up a vigorous response from the neuroscience community. The needs are great: with some form of brain illness or mental disorder likely to strike one in every eight Americans, and with as many as 1,000 different dysfunctions of the brain thought to be determined at least in part by genetic makeup, it is clear that this field of knowledge holds great potential to alleviate illness and suffering, through the clinical tools of diagnosis and treatment and through genetic analysis. The imperative to use our cur-

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DISCOVERING THE BRAIN FIGURE 9.1. Policy decisions concerning the support of research in neuroscience are at least as complex as the scientific field itself. Source: Jerry Van Amerongen, 1984©. Reprinted with special permission of King Features Syndicate, Inc. rent knowledge to these ends, and to continue extending that knowledge, is hardly in doubt. It is in response to the question “What can be done?” that expert opinions diverge, because neuroscience faces far greater opportunities in research than there are resources to carry them out. Research questions that could scarcely have been conceived 10 or 15 years ago, much less investigated fruitfully, can now be explored. The theoretical context—in neurology, in molecular biology, and in genetics—is in place, and the technology—whether in cloning, magnifying, or imaging with pinpoint accuracy—is available. But the likelihood that such investigations can be sustained over a long period is less assured than in the past. True, the strain on resources in neuroscience research can be seen as a measure of success, both in attracting a generation of talented workers and in yielding many lines of inquiry worthy of their attention. But such success must seem a mixed blessing, at best, to the young researcher who hears that these days less than one in four grant proposals may be funded. (Many more than this are of excellent quality and are actually approved, but simply do not rank high enough on the list to receive funding in a time of limited resources.)

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DISCOVERING THE BRAIN DEFINING THE FIELD OF INQUIRY The scope of neuroscience is virtually limitless—it is nothing less than the seeking by the human brain to understand itself. Small wonder that the field draws on other scientific disciplines, some closely related and others that might at first appear more distant: cellular and molecular biology, behavioral sciences, and computational science, but also quantum mechanics and the new field of chaos theory. (This last may soon offer models for some of the processes that take place in integrating information—a task at which the human brain excels.) In addition, neuroscience research in the future will depend more on sophisticated technologies for observing the brain at work and for recording and sorting the flood of information that can be obtained. Computerized databases of neural circuitry—an open archive of the pathways and connections of any of the brain's 100 billion nerve cells—could provide answers and save time for countless research projects. The development of such tools has been proposed by a committee of the Institute of Medicine. Within neuroscience itself, research progresses by means of loops, or back-and-forth exchanges between areas of inquiry that are mutually informative. One of the essential loops occurs between macrobiology and molecular biology; it goes from sophisticated measures of behavior to the precise identification of the nerve cells that underlie a particular movement or perception or memory, and then back again to the animal's behavior. In this connection, it is clear that curtailing the macrobiological studies, under pressure from nonscientists to abandon animal testing, works to the detriment of the whole enterprise; for without behavioral studies as a way of checking theories in the “real world,” cellular or molecular explanations of how the brain works can advance only a short way before sinking into conjecture. Likewise, in the examination of the human brain, the loop between research and clinical practice means that each side provides the other with the tools to proceed further. The study of schizophrenia is a notable example. Clinicians—psychiatrists and psychologists—have assembled the many forms and clinical signs of this disorder under a single heading; molecular biologists and geneticists are tracing patterns of in-

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DISCOVERING THE BRAIN heritance, and neuroscientists have begun to uncover some of the physical abnormalities of the brain that are associated with schizophrenia. This research feeds back into clinical practice by offering more precise criteria for diagnosis. Because neuroscience spans so many fields of investigation, the funding for such research must also be broadly based. In the United States, the federal government disburses about $8 billion annually to support biomedical research, largely through the Public Health Service of the Department of Health and Human Services, which comprises the various National Institutes of Health and the Alcohol, Drug Abuse, and Mental Health Administration. Federal funds also support related projects that are carried out for the Food and Drug Administration and even the Department of Energy. Of this total, about $1.2 billion goes to support research in neuroscience. The Public Health Service is particularly strong in research on mental and addictive disorders, funding almost 85 percent of the nation's efforts in these areas. The federal government' support of brain research is roughly equalled by funding from the private sector—that is, industry, private foundations, voluntary health agencies, and not-for-profit research institutions. Most notable in this last category is the Howard Hughes Medical Institute, which disburses more than $200 million annually for basic biomedical research at about 50 universities around the country; in 1990, it directed about $35 million toward research in neuroscience. Other private foundations that are not devoted exclusively to biomedicine nevertheless contribute substantial sums to basic research: in 1985, the Alfred P. Sloan Foundation gave $9 million, the John D. and Catherine T. MacArthur Foundation $12 million, and the Pew Charitable Trusts $21 million. In addition, a great many smaller foundations support research on a specific disease or disorder; such foundations often begin as one family's personal response to affliction. As the costs of research have increased, the role of industry as a significant source of support has also grown, making it second only to the federal government. Although the pharmaceutical industry, for example, directs nearly 80 percent of its research funds toward product development, it is also farsighted enough to fund both basic and applied research. For example, FIDIA, the fourth-largest pharmaceutical company in Ita-

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DISCOVERING THE BRAIN ly, reinvests 25 percent of its profits each year in a combination of basic and clinical research specifically in neuroscience. In the United States, the pharmaceutical industry as a whole spent about $860 million in 1988 to support research on the central nervous system and sense organs; this figure amounted to almost 15 percent of total sales for that year. SCIENCE EDUCATION AND SCIENCE ADVOCACY At the same time that neuroscience is launched on what could be its most rewarding and exciting decade yet, another challenge is taking shape outside the laboratory—and researchers would be wise to tackle it promptly. This challenge is found in a paradoxical and widespread attitude toward science: the general public depends increasingly on scientific research, and at the same time expresses a growing mistrust of science and its practitioners. Secretary of Health and Human Services Louis Sullivan has said that the general public—particularly the young— often describe science with “four C's”: costly, cruel, corrupt, and closed. For science to bear such an image—even if it is based on ignorance—is unaffordable, by any calculations. Not only the necessity for public support of research but also the steadily growing need to draw bright young minds into the field calls for supporters of science to correct these misperceptions with all due speed. The proper tool to bring about this change is, of course, science education. This can take many forms in addition to what goes on in a classroom—for example, a corporate-sponsored exhibit on the history of neuroscience. And in the mass media, even something as superficial as including scientists among the characters in everyday television programs could contribute toward drawing young people into the field, if the portrayals could be made to avoid the stereotype of the mad scientist or its modern variants (cold and unfeeling, or earnest and unattractive). Frederick Goodwin, of the Alcohol, Drug Abuse, and Mental Health Administration, speaks of “frayed edges around what we used to call scholarship”: the production of data has taken researchers' time away from reaching out to maintain the public understanding of science, from making the best information available to those who teach science in the primary and sec-

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DISCOVERING THE BRAIN ondary schools, and even from explicitly conveying the values of science to those who are considering a career in research. The image of the profession has also suffered from recent examples of misconduct in science. At the same time, formal handling of some cases of misconduct has brought about a clash of cultures, in which an adversarial system—the law—is asked to rule on principles and practices of science that have been shaped largely by consensus. Too often, senior scientists pressed by the multiple demands of high-level research have less time available than they would like for serving as mentors. The current climate may reflect a widespread tendency to pay attention to immediate crises and leave long-term problems to take care of themselves. But this national preference for investing in the short term, says Goodwin, will provide very poorly for the future of science. The federal government should take more of a hand in helping to prepare the next generation in science, and to this end it may be appropriate to fund some of the professional associations or groups that engage in educating the public about science. The small foundations may be the best instruments for presenting the workings of science to the public: they have scientific understanding, motivation, and energy in abundance, combined with resources less extensive than those the federal government can allot to research, but nevertheless substantial. Thomas Langfitt, of the Pew Charitable Trusts, believes that foundations might well be interested in forming better coalitions with the scientific community to convey the value of science, particularly biomedical research, to the nation at large. But such a message cannot be simply stated. It requires careful presentation, because it risks disillusioning a public that may be too anxious about questions of health and well-being to allow plenty of time for thorough research. A basic understanding of the nature of science, inculcated from earliest schooling, could help the public develop more realistic expectations of the scientific enterprise. THE FEDERAL GOVERNMENT AS SPONSOR OF RESEARCH Of all the institutions dedicated to seeing the Decade of the Brain fulfill its promise, the federal government—as befits the

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DISCOVERING THE BRAIN largest sponsor—is pursuing the greatest variety of activities. Within the Department of Health and Human Services, the Public Health Service has singled out four areas of involvement. First is the ongoing support of investigator-initiated biomedical research (as opposed to research assigned by contract) throughout the country. Many of the grant programs of NIH and ADAMHA, in particular, are directed toward investigations in neuroscience. Second, the federal government is in the best position to amass the resources for science projects of all sizes and to coordinate major efforts with those of other countries, as is being done for the human genome project. This long-term multinational initiative, which some researchers have feared might overshadow other projects in biomedicine in terms of public support or funding, is beginning to show its usefulness for numerous research fields outside genetics. For example, it is clear that neuroscience has an interest in the mapping and sequencing of the human genome, since as many as 1,000 of the roughly 3,500 diseases and syndromes known to be carried in the genetic code affect the brain or the nervous system. A third, essential function of the Public Health Service is to clarify the priorities for federally sponsored research in an era of deficit budgets. The fourth function may be the most urgent: developing ways to nurture the next generation of neuroscientists. The Public Health Service is considering incentives for schools and research centers to recruit bright students into the field, and new ways to increase the overall scientific literacy of the public. James Mason, in the Department of Health and Human Services, urges scientists to use the Decade of the Brain to its fullest potential in this regard. The decade offers opportunities on all sides: for conveying the excitement of working in neuroscience and the value of this work to the nation 's health; for raising public awareness of the dangers posed by avoidable injuries of the brain and spinal cord in accidents, by substance abuse, and by the presence of neural toxins in a polluted environment; and, as we come increasingly to appreciate the complexity of the brain, for nourishing the mind as well, by providing every child with a good basic education. In the executive branch, the White House Office of Science and Technology Policy (OSTP) has responsibility for coordi-

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DISCOVERING THE BRAIN nating the many efforts and initiatives that make up the Decade of the Brain. One necessary item is a comprehensive federal plan for supporting research in neuroscience, and to that end OSTP has assembled a working group that includes representatives from government agencies involved in a broad spectrum of brain research. The group also includes representatives from the departments of commerce, education, and state, because the implications from brain research touch on so many areas, even those as far afield as technology transfer, international efforts to promote science, and global competitiveness. A 10-year national research plan for neuroscience would lay the groundwork for the federal government's organization of research funding well into the future. The activities of the Decade of the Brain are directed mainly toward two groups: the public, with the goal of increasing science literacy, and the scientific community, with a long-term research plan as the objective. The OSTP working group has selected eight areas of research for special attention: addiction; aging; development; education, learning, and memory; human behavior and mental disorders; communications and sensory disorders; brain and spinal cord injury; and rehabilitation and restoration of function. The OSTP group wilt use these eight areas as the base for a detailed research plan for the decade, in consultation with federal research agencies, the academic community, and voluntary health organizations. OSTP itself will act as a clearinghouse for resources and efforts from all sectors, fulfilling its traditional role while also contributing to what White House science adviser Allan Bromley calls “one of the most important initiatives that the federal government is undertaking in science and technology in this decade.” A long-term plan may be especially suitable for neuroscience, where the complexity of questions to be addressed and the intricacy of the systems under study can make the research trail very long. Many senior scientists, who must not only plan their own projects but also advise students proposing to enter the field, would like to see stable (or growing) levels of funding from one year to the next. As one participant at the panel discussion remarked, “Scientists like prediction”—but even a scientific prediction is only as good as the information on which it is based. The need for more farsighted planning in

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DISCOVERING THE BRAIN neuroscience is gaining recognition around the world, as other countries —Italy and Canada thus far—consider their own version of the Decade of the Brain. PRIVATE INDUSTRY AND PRIVATE FOUNDATIONS The unusual but highly effective alliance of industry and private foundations makes up a solid base of support for neuroscience. Tightly focused programs sponsored by industry have long been effective. To date, these have been mostly intramural programs—within a company 's own research facilities—but the time is ripe to begin building cooperative extramural programs with the academic, scientific, and medical communities. For some clinical trials, these alliances are already in place. Industry contributes in these cases by continuing to develop sharper measures of efficacy, more powerful theoretical models, and more informative procedures; it also supports clinical research training within the medical community, industry's irreplaceable partner in therapeutic development. FIDIA Pharmaceutical Corporation, for example, is considering whether to establish a number of fellowships for clinical research training in neurology, similar to the corporation's support for basic research. Industry can also help substantially in the area of communications. Alberto Grignolo, president of FIDIA, identifies three target audiences, each needing a distinct message. To the government, industry should carry the message that it is vital to continue to invest in biomedical research—particularly neuroscience research. To the academic community, industry needs to convey its interest in collaborating on the best possible research and in translating knowledge into therapeutic advances. And to the public, industry should clearly announce and reiterate that better diagnoses and new treatments depend on continued investment in both basic and applied research. In contrast to the broad reach of industry, the aims of private foundations tend to be more narrowly focused. A foundation with a research budget of, say, several million dollars per year for neuroscience finds itself in an interesting niche. Clearly, it cannot compete with the federal government in funding worthy projects, nor can it necessarily command the expertise

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DISCOVERING THE BRAIN and resources needed to run an effective peer-review system for selecting those projects. What such a foundation does instead is create (or skillfully discover) those research initiatives that are of high quality but that are unlikely to receive funding through conventional channels. Thomas Langfitt, of the Pew Charitable Trusts, says there are two likely reasons a promising application for funding might be turned down by NIH or another federal research agency. First, the research may seem too risky—often simply because it is at too early a stage for the outcome to be clearly predictable. Second, it may be too interdisciplinary, that is, not strictly within the bounds of one scientific field or another and thus difficult to evaluate. Yet if research of this kind can obtain support from a private foundation at an early stage, the work may well go on to win approval from a government research agency later on. With this reasoning, the Pew Trusts have recently launched two initiatives for funding in neuroscience. One is aimed at bringing basic research and clinical practice closer together in neuroscience; the other is designed to foster cross-disciplinary thinking—that is, to encourage a wide variety of traditionally unrelated fields (cognitive psychology, primate behavior, computer science, linguistics, philosophy) to contribute to neuroscience and to be enriched by it in turn. The Pew Trusts have also awarded grants to laboratories for the development of cell lines of neural tissue—an emerging need among research departments of medical institutions. The cross-disciplinary initiative, the McDonell-Pew Cognitive Neuroscience Program, focuses on research and training, awarding funds to research centers at several institutions and also disbursing a number of smaller grants each year. This program makes a particular effort to enlist researchers who are already well under way in their field—graduate students or postdoctoral fellows—and who know they will need to become familiar with at least one other discipline to pursue their line of interest. The exchange thus fostered should help to give cognitive neuroscience the broadest possible base for exploring the subtle, intricate relationship between the human mind and its physical counterpart, the brain. A small private foundation can effectively support neuro-

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DISCOVERING THE BRAIN science by promoting research on just one or two disorders. The National Alliance for Research on Schizophrenia and Depression (NARSAD) is an example of this approach; the alliance currently funds several dozen investigators, primarily in their early years of research, awarding more than $3.5 million in grants. Applications for grants are not as complex as those required by federal funding agencies but nevertheless undergo first-rate peer review, thanks to a number of eminent scientists who donate their time. Despite its limited resources, the alliance is clearly meeting a need: its small-grants program attracts between 600 and 700 applications per year. A foundation oriented toward public relations, such as the David Mahoney Institute for the Decade of the Brain, may favor a broader approach. This not-for-profit group was founded by nonscientists, with an advisory board drawn from science, business, and the media. David Mahoney sees the institute 's mission as helping to “coordinate, orchestrate, and unify the efforts of all interested parties in support of the Decade of the Brain”—in essence, an institute for public education. A FUTURE RICH WITH CHALLENGES Explaining neuroscience to the public poses special difficulties. For one thing, in any specific area of research, the complexity of the system under study is hard to take in. We cannot readily envision 1011 nerve cells, even when we are told we carry them around inside our head—or perhaps especially when we are told this. In addition, many people already have quite definite ideas about how their mind works, ideas in which values such as free will and independence of action may play a large part. When a scientific explanation appears to overlook these values and presents instead an account that is highly complex and based on invisible principles (or invisibly small molecules), it may well meet with some resistance. But not all the odds are stacked against neuroscience. An important human factor that works to its advantage is that everyone is interested, at one time or another, in finding out about the workings of his or her brain. Similarly, public concern about the social ills of substance abuse, a concern now as

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DISCOVERING THE BRAIN widespread as the afflictions themselves, could be the opening needed to convince the public of the importance of brain research for understanding and treating addictions. A simple way to measure the health of a scientific discipline might be to ask a gathering of its practitioners, “Would you encourage your best young students to enter the field nowadays?” Allan Bromley, while traveling around the country and meeting with groups in many scientific fields, has found that the answer tends to be no, and the reason often given is that the particular field under discussion is not as much fun as it used to be. For neuroscience, the answer was a little different. Some said no, just as many said yes, and perhaps the greatest number emphatically answered both yes and no. Surprisingly, a clear consensus emerged from all this: while the science itself is more exciting than ever and the practical applications of one's work may be most gratifying, finding subsistence in the field has become more and more difficult and time consuming, and the prospects are discouraging. A senior scientist may well hesitate before encouraging young investigators to enter the field—particularly if the funding prospects to sustain a career show no signs of improving and a scientist's time is increasingly taken up with the search for funds rather than with research. The long-time chairman of one neurology department put the matter succinctly: “The doing is sensational now. It's the not doing that's agony.” Huda Akil, of the Mental Health Research Institute at the University of Michigan, suggests that research groups or “teams” may offer young researchers some protection against too-early exposure to the fierce struggle for funds. With a senior scientist navigating the grant application process, young researchers are free to concentrate on their work. Although in no way a long-term solution to constraints in funding, the team approach offers at least partial shelter and makes use of the assurance and standing of researchers who have already spent some time in the field. It is a simple but ironic sign of the times that neuroscience should be facing some of the greatest research challenges the field has ever seen just when it is becoming clear that there may no longer be the resources to tackle them as they deserve.

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DISCOVERING THE BRAIN The knowledge gained from past decades coupled with today's powerful technologies for imaging, magnifying, assembling data, and cloning cells make for fascinating research possibilities; the means for translating research findings into therapeutic benefits are increasing all the time; but budgets have rarely been so tight. Public funds are being strained to the limit—and still the list of social ills continues to grow, increasing the competition for these strained resources. In a society struggling with a weak domestic economy, a decline in public education, the deterioration of cities, and a staggering one-fifth of the population living in poverty, science must make the broadest possible case for what it can contribute toward healing these ills. Public support for brain research in the near future may depend on the success with which the scientific and health care communities, and other parties sympathetic to their aims, can convey the excitement, the fascination, and above all the public value of neuroscience. The time is right for building alliances between the public and private sectors that can bring the research agenda, talent, funding, and logistical support for these efforts all together. Neuroscience is poised for dazzling progress in the next 10 years. ACKNOWLEDGMENTS Chapter 9is based on a panel discussion entitled, “In the Coming Decade: What Needs To Be Done? What Can Be Done?” The panelists were D. Allan Bromley, assistant to the President for science and technology; Pete V. Domenici, United States senator; Frederick K. Goodwin, administrator of the Alcohol, Drug Abuse, and Mental Health Administration (ADAMHA); Alberto Grignolo, president of FIDIA Pharmaceutical Corporation; Thomas W. Langfitt, president of the Pew Charitable Trusts; James O. Mason, assistant secretary for health in the Department of Health and Human Services; and David T. Mahoney, president of David Mahoney Ventures and chairman of the Dana Foundations.

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