Neuroscience and the private sector: A necessary alliance

ePspect ves that, although chemically distinct, serve the same general purpose of providing a regulatory link between targets and the nerve cells that innervate them. Understanding the rules that govern the competition for these agents and their effects on neural organization in health and disease seem likely to preoccupy neurobiologists for several decades. Given this prospect, it is clear that the Nobel Committee was entirely justified in honoring LeviMontalcini and Cohen in 1986. Whether the Committee acted fairly in excluding Viktor Hamburger, however, will be debated. Our present understanding of growth factors in the nervous system, and the current search for new factors, are based on two intertwined themes: the general concept that neurons depend on their targets for survival and the particular example of NGF. Whereas LeviMontalcini's remarkable work has appropriately identified her as the discoverer of NGF and the person who elucidated its biological role, it should be apparent from the history outlined here that Hamburger's contributions to both themes were also crucial.

Selected references 1 Hamburger, V. (1942) A Manual of Experimental Embryology, University of Chicago Press 2 Hamburger, V. and Hamilton, H. (1951) J./Vlorphol. 88, 4992 3 Shorey, M. L. (1909) J. Exp. Zool. 7, 25-63 4 Hamburger, V. (1934) J. Exp. Zool. 68, 449-494 5 Hamburger, V. (1939) Physiol. Zool. 12,268-284 6 Levi-Montalcini, R. (1975) in The Neurosciences: Paths of Discovery (Worden, F. G., Swazey, J. P. and Adelman, G., eds), pp. 244-265, MIT Press 7 Levi-Montalcini, R. and Levi, G. (1942) Arch. Biol. 53,537545 8 Levi-Montalcini, R. and Levi, G. (1944) Pontiff Accad. Sci. Commentat. 8, 537-545 9 Hamburger, V. and Levi-Montalcini, R. (1949) J. Exp. ZooL 111,457-502 10 Bueker, E. D. (1943) J. Exp. Zool. 93, 99-129 11 Bueker, E. D. (1948)Anat. Rec. 102, 369-390 12 Bueker, E. (1985) NYU Physician, Fall Issue, 14-16 13 Levi-Montalcini, R. and Hamburger, V. (1951) J. Exp. ZooL 116, 321-362

14 Levi-Montalcini, R. and Hamburger, V. (1953) J. Exp. Zool. 123,233-288 15 Levi-Montalcini, R., Meyer, H. and Hamburger, V. (1954) Cancer Res. 14, 49-57 16 Levi-Montalcini, R. (1953) Proc. XIV Int. Congr. Zool. Copenhagen: 309 17 Cohen, S., Levi-Montalcini, R. and Hamburger, V. (1954) Proc. Natl Acad. Sci. USA 40, 1014-1018 18 Levi-Montalcini, R. and Cohen, S. (1956) Proc. NatlAcad. Sci. USA 42,695-699 19 Cohen, S. and Levi-Montalcini, R. (1956) Proc. NatlAcad. Sci. USA 42, 571-574 20 Cohen, S. (1959) J. Biol. Chem. 234, 1129-1137 21 Cohen, S. (1960) Proc. NatlAcad. $ci. USA 46, 302-311 22 Greene, L. A. and Shooter, E. M. (1985) Annu. Rev. Neurosci. 3, 353-402 23 Levi-Montalcini, R. and Calissano,P. (1986) Trends Neurosci. 9, 473-477 24 Hamburger, V. (1970) in The Neurosciences: Second Study Program (Schmitt, F.O., ed.), pp. 141-151, Rockefeller University Press 25 Hamburger, V. (1973) in Studies on the Development of Behavior and the Nervous System (Gottlieb, G., ed.), pp. 5176, Academic Press 26 Hollyday, M. and Hamburger, V. (1976) J. Comp. Neurol. 170, 311-320 27 Brunso-Bechtold, J. K. and Hamburger, V. (1979) Proc. Natl Acad. Sci. USA 76, 1494-1496 28 Hamburger, V., Brunso-Bechtold, J. K. and Yip, J. (1981) J. Neurosci. 1, 60-71 29 Hamburger, V. and Yip, J. W. (1984) J. Neurosci. 4, 767-774 30 Carpenter, G. and Cohen, S. (1979)Annu. Rev. Biochem. 48, 193-216 31 James, R. and Bradshaw, R. A. (1984) Annu. Rev. Biochem. 53,259-292 32 Hunter, T. and Cooper, J. A. (1985) Annu. Rev. Biochem. 54, 897-930 33 Levi-Montalcini, R. and Booker, B. (1960) Proc. Natl Acad. Sci. USA 45, 384-391 34 Levi-Montalcini, R. and Booker, B. (1960) Proc. Natl Acad. Sci. USA 46, 373-384 35 Levi-Montalcini, R. (1982)Annu. Rev. Neurosci. 5, 341-362 36 Thoenen, H. and Barde, Y. A. (1980) Physiol. Rev. 60, 12541335 37 Shelton, D. and Reichardt, L. F. (1984) Proc. NatlAcad. Sci. USA 81, 7951-7955 38 Heumann, R., Korsching, S., Scott, J. and Thoenen, H. (1984) EMBO J. 3, 3183-3189 39 Berg, D. K. (1984)Annu. Rev. Neurosci. 7, 149-170 40 Barde, Y. A., Edgar, D. and Thoenen, H. (1983) Annu. Rev. Physiol. 45, 601-612 41 Slack, J. R., Hopkins, W. G. and Pockett, S. (1983) Muscle Nerv. 6, 243-252

Neurosdenceand the private sector: a necessaryalliance Nancy S. Wexler The organizations included in the list that follows this article concern themselves with disorders that come under the mandate of the National Institute for Neurological, Communicative Disorders and Stroke (NINCDS), of the National Institutes of Health (NIH). The extraordinary range and diversity of the illnesses that lay claim to the Institute's attention can be seen in this directory. Some organizations are small and specific to one disease; others are large and more inclusive. Some serve only a few suffering from a rare affliction; others have a constituency that is a sizeable percentage of the population. The voluntary health movement is so much a part of the US national scene, so reasonable TINS, Vol. 10, No. 6, 1987

a response on the part of concerned patients and families, that we tend to take them for granted. The National Institutes of Health and their respective voluntary health agencies appear to coexist symbiotically like a life form that has evolved over millenia. It is easy to forget that both the public and the private institutions dedicated to improving health through biomedical research are relatively recent innovations, fomented by a scientific revolution beginning after World War II and continuing until the present time. The NIH, so imposing and seemingly permanent a bastion of the government, barely existed 40 years ago, and private sector organizations, the very few that there were, had

© 1987,ElsevierPublications.Cambridge 0378-5912/87/$02.00

Nancy Wexleris the Presidentof the Hereditary Disease Foundation,606 Wiltshire Boulevard, Suite504, Santa Monica, CA90401, USA.

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little scientific impact and viewed the government with suspicion. Any discussion of the role of the private sector in health must surely include the Laskers, two citizens who helped to create the federal and voluntary institutions we know today. In the mid 1940s, Mary and Albert Lasker set in motion forces that revolutionized the public and private sectors in health. Albert Lasker developed many of the principles underlying modern advertising techniques (and ironically made his fortune promoting tobacco companies long before the health threat of cigarettes was known). He and his wife Mary Woodward Lasker, a businesswoman and art connoisseur, were horrified to learn that in 1944 the government spent only $560000 a year on cancer and nothing on heart disease, neurological disorders, mental illness or any other of the 'killers and cripplers', as the Laskers described the major debilitating illnesses of our day. The US Public Health Service had established the National Institute (singular) of Health and the Cancer Institute, which served as its research arm, but in 1944 the total federal budget for research in all illnesses was only $2 400 000 a year. Appalled, the Laskers set about to increase this figure. They enlisted the help of other concerned citizens and approached Senator (now Congressman) Claude Pepper from Florida, who was immediately sympathetic. Soon Pepper was holding congressional hearings on the need for increased biomedical research and recruiting others in the government to help him build a research capacity 1. The Laskers were dedicated to the belief that only the Federal government could provide the massive infusion of funds necessary to ignite and support new areas of science. They were tireless in their efforts to persuade Congress of this vision; Mary Lasker traveled to Capitol Hill 27 times one year. Today the budget of the National Institutes of Health (of which there are twelve) is somewhat over $6 billion. While never relenting in their federal committments, the Laskers also fundamentally changed the form and function of existing private sector health agencies, notably Planned Parenthood and the American Cancer Society. From small, rather ineffectual organizations, allergic to government intervention and unwilling to fund research, these groups were galvanised by the Laskers to become prestigious institutions with substantial budgets, strong research committments and effective lobbying skills for obtaining additional federal money for the NIH. The Laskers' most notable success in the private sector is the inimitable Albert and Mary Lasker Foundation, founded in 1942. Each year an outstanding achievement in basic and clinical research and, in most years, in public health is recognized by receipt of the prestigious Lasker Award. According to Lewis Thomas who wrote a recent review of the awards, 'Looking back, the history of the Lasker Awards since 1946 can be read as an accurate record of the progress of biomedical science over the past 40 years '~. The prescience of the deciding 236

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committees and juries must also be applauded. One third of all Lasker Award winners have gone on to receive Nobel Prizes for their work. The Albert and Mary Lasker Foundation continues to open new areas of science and to foster a dialogue between Congress and the private sector. The Albert and Mary Lasker Foundation is by no means a typical private sector organization, but its uniqueness and its accomplishments have served to inspire many others who share its goals to reduce disease and disability. Most voluntary health agencies follow in the pathway blazed by the Laskers to Capitol Hill. Here agencies argue, usually effectively, for the funds needed by the NIH. Families are willing to bare their souls in testimony, to bring disabled relatives to the hearing rooms, to bring the reality of their despair before Congress. In many instances, an Institute director is prohibited from telling Congressmen the truth about increasing research needs. As part of the executive branch, the NIH leadership must give the figures in their public requests that the Office of Management and Budget dictates, regardless of their validity. Private sector agencies are not so constrained. It is the voluntary agency's responsibility to make sure that Congress has access to all the statistics. Most scientists are unaccustomed to think a great deal about the 'lobbying' or Congressional educational activities of the voluntary health organizations, yet they are critical for the scientist's career for two important reasons. First, Congress usually increases the NIH appropriation over the budget of the President in response to citizen pressure. And secondly, scientists who lobby are sometimes viewed sceptically, since some in Congress see them as having a vested interest. Affected families have credibility. While scientists may be seen as protecting their livelihoods, families are seen as protecting their lives. Most voluntary health organizations have their own programs of research funding. Some are entirely dedicated to scientific support, such as the Hereditary Disease Foundation and the McKnight Foundation, while others support a mixture of grant programs and patient services, such as the National Multiple Sclerosis Society and the Epilepsy Foundation of America. Many agencies give postdoctoral fellowships as well as research grants. A number of the larger organizations, such as the Muscular Dystrophy Society and the March of Dimes Birth Defects Foundation, can give grants commensurate with NIH levels of funding. Most agencies, however, give 'seed money' support, small grants that allow an investigator to begin a project, develop pilot data, test an idea before committing to a particular direction, or learn a new technology. Two $20000 grants might represent half of an agency's total annual budget. But the hope generated by these grants will carry the agency through the year. For the scientist, the availability of flexible money can be worth far more than the actual dollars. Money from 'the voluntaries', as they are often called, can enable a scientist to pursue an inspiraTINS, VoL 10, No. 6, 1987

tion, or to take advantage of surprise and serendipity in science. According to Lewis Thomas, 'the driving force in good science, moving any field along from one discovery to the next, is surprise. The highest achievements in science have come from scientists with an inborn gift for recognizing a real surprise when they encounter one, then acting on it, following wherever it leads them '2. The voluntary health agencies have the capacity to move quickly when necessary, to be flexible, and to take chances. Government funding is more ponderous, with nearly a year between submission of a grant and awarding of funds. As federal dollars tighten, the willingness of review committees to be speculative may also constrict. A private agency pursuing the cure of a disease is often willing to go with a long shot. The stakes are different. Private foundations can also play an important role in stimulating new research hypotheses. Many foundations will convene meetings or help cosponsor symposia with the NIH or professional societies. A few organize true 'working' workshops. The Hereditary Disease Foundation has developed a program of interdisciplinary workshops which, in my experience, is unique among voluntary health organizations. Foundation workshops evolved from the observations of our early advisors that the best and liveliest exchanges in scientific meetings take place in between formal sessions, in the intertices of prescribed scientific interactions. Only fifteen or twenty people from varied scientific disciplines attend the workshops, there is a mix of senior investigators and postdoctoral students, and slides are prohibited. Participants explore how their particular expertise can shed light on problems of hereditary neurodegenerative disease. Research projects conceived in the workshops can then be funded through the Foundation's grant program. The Hereditary Disease Foundation is also immersed in another experiment in fostering science. The 'Collaborative Agreement' is a grant program to investigators in seven different laboratories in the USA and Europe who have joined in a collaborative effort to isolate and characterize the Huntington's disease gene using the varying technologies that they are developing. These strategies are being focused on the HD gene so that they will be more easily applied to the discovery of other genes as well. Even without large sums of research money, voluntary health agencies can perform a great service by acting as intermediaries, brokers between the scientists and the resources needed for research. Neuroscientists often require brain tissue from normal and diseased brains. The agencies can organize tissue collection procedures, intervene with families and pathologists and even establish or help support tissue banks that can provide investigators with critical and scarce tissues. The National Multiple Sclerosis Society, Scottish Rite and the Hereditary Disease Foundation collaborate with the government in the support of two tissue banks. Voluntary health organizations can also help to find research subjects and will usually make the initial contact with patients and families to solicit TINS, Vol. 10, No. 6, 1987

their cooperation. Often only the agency knows where a particular type of research subject may be, such as newly diagnosed or unmedicated patients. Recent breakthoughs in the localization of genes for Huntington's disease, familial Alzheimer's disease and manic-depressive disorder have underscored the necessity for studying large, wellcharacterized and cooperative families with a genetic disorder. Once a gene has been localized in one family, additional families are then necessary to determine if there is genetic heterogeneity, one gene or many. Voluntary health organizations frequently know where large families are located and again can serve as intermediaries. They can also, as with other research requests, advertise in the often excellent newsletters that most groups produce for their membership. A final tie between scientists and voluntary health organizations is a more intangible, more powerful psychological bond. Most agencies are founded and run by families concerned with a particular disease. For them, the scientist is the clearest symbol of hope. Research grant money is scraped together from bake sales, raffles, or cannisters in shopping malls. Improved services may be one goal to improve the quality of life for a patient, but basic and clinical research into the cause, treatment, prevention and cure of an illness is the beacon that guides and sustains an organization. To patients or relatives or friends of someone afflicted, the willingness of scientists to be interested in 'their' disease, to spend time, thought and effort in understanding it is like food for the starving. Agency memberships often adopt 'their' investigators into the organizational family, beaming with pride and interest during the obligatory science lectures even though the words may be unintelligible. And from the scientist's perspective, the solicitude and appreciation of families can add a relevance and an urgency to research, that is very rewarding. Particularly for basic scientists who sometimes feel isolated in their laboratories, perceiving the importance of their work for potentially ameliorating a devastating illness can give it added dimension. Members of the 'voluntaries' are racing against a clock that may be running out for a relative, a friend, or themselves. That clock pushes them up Capitol Hill, pushes them to raise funds, pushes them to seek the best and brightest scientists who hold the future in their imaginations. And the scientists find themselves pushed by the scientific questions and by the fact that their work matters so much to these individuals. The human element, the relationships between scientists and agencies, the chemistry between the investigators and the investigated is powerful. They need each other, the voluntaries and the scientists. And when the relationships go well, they are uniquely satisfying. Selected references 1 Gunther, J. (1960) Taken at the Flood: The Story of Albert D. Lasker, Harper & Brothers 2 Thomas, L. (1986) The Lasker Awards: Four Decades of Scientific Medical Progress, Raven Press 237