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Dll DEVELOPMENTS IN REDR.OSCIENCE: HISTORICAL AND El'BICAL ISsm:s IN NEURAL TRANSPLANTS Rosa Lynn Pinkus, Ph.D. Associate Professor Department of Neurosurgery University of Pittsburgh Pittsburgh, PA Final Draft Do Not Quote Without Permission By Author This paper was written under support of the Office of Technology Assessment, Contract J3-4960.0, who maintain copyright privileges. This contractor document was prepared for the OTA assessment Neural Graftin2: Repairin2 the Brain and Spinal Cord. This document does not necessarily reflect the analytical findings of OT A, the Advisory Panel, or the Technology Assessment Board. References to this dnct1ment shm11d cite the contractor. not OTA. as the author.
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Nm DEVELOPMENTS IN NEUROSCIENCE: HISTORICAL AND E"l'BICAL ISSUES IR REDRAL TRARSPLARTS INTRODUCfION AND CONTEMPORARY BACKGROUND This paper investigates a complex and little studied topic in the history of medicine. It explores the social and intellectual context surrounding advances in neuroscience leading to the recent application of neural tissue transplantation to treat patients having the intractable and incapacitating Parkinson's disease (Madrazo, 1987; 1988). Relying heavily on the factual information presented in the historical overviews of two introductory texts on neural transplants (Gash, 1984; Bjorklund, 1985), it places the persons therein identified, and the data obtained from their investigations within a broad historical context. It also brings to light new information not discussed in the previous reviews. Thomas Kuhn, a philosopher of science whose work has centered on how revolutions take place in science generally, is hesitant to specify merely a chronology of events when he discusses scientific progress. Kuhn insists that the explanation of progress Must be a description of a value system, an ideology together with an analysis of the institutions through which that system is transmitted and enforced ... Knowing what scientists value, we may hope to understand what problems they will undertake and what choices they will make in particular circumstances (Kuhn, 1962; 1977). Given this approach, a complex story unfolds, not unlike others documented in medical science, which helps to explain how 1
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technology, scientific facts, professional attitudes and institutions combined to interact in a practical sphere to set the stage for current clinical trials (Barber, 1961; Co~roe, 1978). Intellectual ideas about abstract but perennial issues related to mind/body concepts are also considered. They are considered, however, from the viewpoint of the neuroscientist. That is, philosophical debate regarding these issues are discussed only when ~hey raise practical issues for the scientist. Given this perspective, one can begin to appreciate when, where and in what manner general underlying concepts directing scientific investigation were questioned and "readjusted." Essentially three "levels" of historical information are presented. First, the particular names and dates o.f' individuals provide a chronological time-line. Second, refere~ce is made to trends such as urbanization, political shifts and technological developments. These tend to be recognized by specific individuals and helped to shape their actions. The third level is the most abstract. The hundred year shifts in thought which we can only view from our present stance. Contemporaries had no way to detect these. Some, however, recognized that their observations outstripped current concerns, and accordingly, they held explanations at bay. Basically, the period in history covered in this paper spans the years 1830-present. Specific time periods, however, are explored in depth, while others are merely sketched. The aim is to provide one broad sweep, looking closely at times so as to 2 : ....
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understand what is known and also to point to areas deserving of future investigation. The years 1830-1850, when phrenologists directed attention to particular locations on the contour of the cerebral cortex as a mediator of particular activities is actually a starting point to this investigation. Their quaries involved notions such as "wills" and "moral faculties." They corralled the soul and directed it to the brain. This crude materialism was popular for a time but clashed head on with the developing factual study of the brain conducted by experimental neurologists. From 1850-1890, the classic study of localization of brain function was carried on within a conceptual framework which pragmatically separated mind and body into different disciplines: neurology and psychology. "Mental events" were regarded as existing in parallel with observed brain functions. Under this guise, ~twas considered "scientific blasphemy" to join the two. The years 1890-1920 are the years in which the first importanc studies in neural transplantation in mammals were conducted. lJhile no overt concept change regarding mind/brain interaction was made, these years are typically considered years of intellectual "accommodation" to the previous decades polarized views. W. Gilman Thompson (Gilman, 1890), S.Y. Ranson (Ranson, 1909; 1914) and Elizabeth Hopkins Dunn (Dunn, 1917) are the three American researcher~ identified in previous studies as heralding experiments in neural tissue transplantation. They directed attention to transplantation as a technique; proved that it was possible if fetal tissue were used and if tissue were transplanted 3
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close to a rich blood supply. Other European scientists are identified such as Saltykow, 1903, at the University of Basil; J. Fossman, Sweden, 1898; G. Del Conte, Italy, 1907; and F. Tello, Spain, 1911. The careful histological studies of the brain and the neurone theory conceptualized by Ramon y Cajal in 1906 also contributed a set of questions and observations for researchers to consider .and study. In spite of the impressive and careful experimental work done in the late nineteenth and eArly twentieth centuries, neural tran~~lantation proved to be an innovative tachnology which lay fallow for approximately 70 years (Gash, 1984; Bjorklund, 1985). Both Gash and Bjorklund have identified this pattem and point to several factors to explain why it occurred. Technical developments which ensure long-term graft survival,. were not available in the early part of the century. The abillty to identify neurotransmitters such as dopamine, norepinephrine and serotonin did not exist until 1962 (Figure 1). Thus, a sufficient rationale for pursuing the experiments was lacking. That is, transplants were not considered clinically significant but were limited to defining the anatomic structure of nervous tissue. Both Gash and Bjorklund point also to the fact that concepts in what we now call the "neur~sciences" in the late nineteenth and early twentieth centuries "negated the consideration of functional transplants" (Gash, 1984). These explanations partially explain why neural transplantation technology met such a bleak future in 1917. 4
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Midbrain of a 45-year-old woman widl P:ark.inson 's syndrome, showing depigmeawion of substantia nigra. .._ IC:0MTI OOHI OH ----~ CfM:1 NCC00M I NH~ DOPA !:DICAAIIOVU,91 OMD'HVLDOPA OoMlow __ V OCPAMINC ..,.o,noi111 --==---
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Concepts in neuroscience underwent a profound change from approximately 1970-present. There were sporadic contributions made to neural transplantation from 1920 onward, such as Y. Shirai, 1921, G. Faldino, 1924, Y.E. Le Gross Clark, 1940 and B. Flerko and J. Szentagothal, 1956. Yet, it was not until knowledge of the nervous system at the ri~chemical level suggested a possible functional use of transplantation that a rapid program of experimentation began. (See Figure 2.) Generally, the research during these years covered four questions: To what extent do grafts survive? Do surviving cells manifest normal growth patterns regarding size, shape, geometric cytoarchitecture'l Do these cells extend dendrite-axonal axis to host brain? (i.e.) is there such an entity as "reciprocal connectivity? Do grafted cells alter the function of the adult brain? It was the pursuit of these questions experimentally that led to Madrazo's clinical trial (Madrazo, 1987, 1988). In the April 6, 1987, issue of the prestigious New England Journal of Medicine, Madrazo et al. described autotransplanting fragments of adrenal medulla tissue in the right caudate nucleus of two patients with intractable and incapacitating Parkinson's disease. Both patients reportedly experienced rapid and dramatic results: rigidity and akinesia virtually disappeared and the tremors characteristic of Parkinson's disease were greatly reduced. The authors, limited by lack of long-term follow-up, described their results as preliminary and urged that further work be done to determine both the long-term efficacy of the procedure and its 5
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2QOOO l,S.000 10.000 S,000 /.I .-' ./ ,-,-----1900 1910 1920 1930 If AO 1950 1960 1970 1910 YEARS Figure 2. The number of papers indexed under the "Nervous System" and related headings in Index Medicus are shown for the first year in each decade from 1890 to 1960. Similar data, in this case from papers listed in the "Nervous System" (AS) category of Index Medicus, are shown for each year from 1967 to 1980. Gash, 1984
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application to other patients (Madrazo, 1987). Ten months later, these same authors published a short letter to the editor, again in the New England Journal of MediciM which stated that in their now "wide experience with autografting" they observed a high morbidity and mortality rate in patients over 60 years of age. They reasoned that th~ two major simultaneous operations, a laparotomy and craniotomy needed to carry out autotransplantatiott, caused these poor results. Citing the -successful laboratory work derived from transplanting fetal tissue in various animal models (Bjorklund, Steveni, 1985), the authors concluded that "transplants of human fetal tissue could be an alternative in older patients and reported preliminary results of ,mil, procedure in two patients (Madrazo, 1988). One and a half years after Madra%o's initial publication approximately 100 patients having intractable Parkinson's disease were operated upon largely at five university centers. The results, however, are discouraging. "Parkinson Procedure: Fervor Turns to Disillusion read the headline in an April 1988 New York Times article. Documenting costly and dangerous complicatio~s, clinicians have questioned Madrazo's statistics and the efficacy of adrenal medulla transplants--particularly in older patients. Repeating the observations made by Madrazo in January, they have begun to look to fetal transplants as a possible option. Responding to a mandate for societal consensus on~ controversial issue, the Department of Health and Human Services convened in September 1988 a committee from NIH to advise it on 6
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the ethics and legalities of the medical procedure involving the use of fetal tissue. The prestigious NIH was criticized as "packing" the study panel for closing its doors to public scrutiny (American Medical News, 1988) during one day of the meetings. Undaunted, the panal met again in October and issued a temporary report granting permission to use fetal tissue obt6ined from preplanned abortions. Guidelines are to be finalized in December 1988 (Biolaw, 1988). The rapid succession of events which followed publication of Madrazo's work are difficult to analyze. While clinical ethicists have provided thoughtful and rigorous comment regarding specific issues (Caplan, 1987; Mahowald, 1986), perhaps by taking a step back and gaining a long-term perspective, we can identify developments which were involved in previous attempts to develop neural tissue transplantation. This will, hopefully, illuminate factors relevant to investigation directed at assessing its current use. HISTORICAL BACKGROUND 1830-1890: FROM PHRENOLOGY TO NEUROPHYSIOLOGY The spurious contribution to neurology made by Franz Joseph Gall, 1759-1828, provides a starting point to assess current developments in neuroscience (Gall, 1835). Postulating that the brain was the organ of the mind, Gall, an anatomist, developed his science of cranioscopy in England in the 1790s. Better known as Phrenology, this new theory displaced the medieval concept of the "unsubstantiated soul" with a notion that mental and moral 7 f/
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faculties could be identified by inspecting the brain's surface. The idea of being able to exercise one's "will and hence change one's character was particularly appealing to both English and American cul~ure in the 1840s and 1850s (Spurzheim, 1834). This was a time wli.en the physician's harsh treatment by purging, bleeding, usi1,g emetics and doses of calomel came severely into question. Natural healing, self help cures and home medical remedies flourished (Shryock, 1936; Sigarest, 1945). Representing sentiments associated with the close community ties of a fast vanishing rural, small town existence, phrenology was quite popular for these two decades, and in some spheres, lingered well into the twentieth century (Mclaren, 1924; Parssinen, 1974; Schwartz, 1952; Wrobel, 1975). Reflecting the divisive nature of the medical profession during the 1850s, 1860s and 1870s, European-educated, urban-based neurologists began to question the appropriateness of physicians, like J.S. Jewell locating the "seat of uoral sensibility" in the "envelope of grey matter on its outer surface called the cortex" or of calling "irresistible impulses" diseases (Geller, 1986; Shryock, 1936). Critics of the concept held in common a belief in organic etiology. They regarded concepts such as "will," "propensities to lust or arson," and "faculties of the mind" as "scientific blasphemy." The brain, they argued, was not the "seat of moral responsibility" but the "integrator" of sensory-motor phenomenon. John Hughlings Jackson, 1835-1911, was an influential proponent of this philosophy. 8 .,I~
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In a round about way, Jackson and his eminent colleagues derived great benefit from Gall's work. Phrenologists, were the first modern investigators to raise the question: "Could particular activities be mediated by the cerebral cortex and localized to specific regions?" Their subsequent theory "while essentially wrong, was just right enough to further scientific thought" (Boring, 1963). It did so by directing attention to the anatomy of the convolutions and gyri of the brain and by providing anatomists with an imperative for studying neuroanatomy. By 1860, minute illustrations of the surface of the brain existed and the question "iJhat did they do?" became paramount (Boring, 1963; Clark and Dewhurst, 1974; Young, 1970). The documentation of what the convolutions did is a familiar and classic phase in the history of cerebral localization. The work of Gustav Theodor Fritsch, 1838-1927, David Ferrier ,1843-1928, Eduard Hitzig, 1838-1907, Pierre Broca, 1824-1880, C. Sherrington, 1857-1952, and John Hughlings Jackson, 1835-1911, have all been reviewed elsewhere ( Churchland, 1986; Clark and Dewhurst, 1974; Harrington, 1987; Young, 1970). Concentration here will be directed to John Hughlings Jackson's philosophical contributions to the neurosciences. He is in large part responsible for framing a conceptual base from which modern neurologists, neurosurgeons and psychiatrists have perceived the mind/body problem. While there are still basic historical questions unanswered about Jackson's contributions, the following conveys what is known (Greenblatt, 1965, 1970, 1977; Harrington, 9 ,/ ,(
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1987). Jackson was a product of his times and was the recipient of a wide range of ideas: all of which he wrote about in a verbose and convoluted style. He was not the only or the most important contributor to underpinnings of the neurosciences. Nevertheless, Jackson symbolized the scientifie materialism prevalent during the nineteenth century. Disparaging the tradition of Franz Gall, Jackson sought to distinguish be~#een psychological and physiological knowledge. He p:oposed that the nervous system was no longer the organ of the ,oul but in the tradition of his fellow neurologist Sherrington: the organ of sensory-motor integration. "If physical enterprises such as medicine and neurology are to succeed," wrote Jackson, they must remain consistently materialistic in the handling of their data (Engelhardt, 1975). In short, if one were to say that the mind caused a physical state, one would be introducing an alien element into an otherwise closed system. Psycho-motor phenomena, according to Jackson, were scientific blasphemy. The brain was described and studied in terms of sensory-m,otor performance: a field that physiology was competent to study. Jackson called this division of the mind and body the Theory of Concomitance .. For him, the doctrine prohibited reduction of psychological events to physiological processes. He created a paradigm which isolated neurology from psychology, eliminated phrenology and replaced it with physiological concepts (Engelhardt, 1979). Jackson's paradigm reflected a specific philosophicul 10
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approach: that which was defined by Herbert Spencer, 1820-1903, an independently wealthy and controversial English social theorist. Spencer's sociology was overwhelmingly popular in both England and American in the mid 1850s, but by 1890, met with severe criticism, as it was too rigid in its theoretical predictions (Haskell, 1977: Paradis, 1981: Turner, 1985). Spencer was an evolutionist whose theories predated Darwin yet matured in a post-Darwinian environment. In his first book, Social Statics (1851), he coined the phrase survival of the fittest" and laid the groundwork for his praise of laissez faire and his acceptance of its social consequences. Spencer viewed societies (indeed, individuals, institutions and the nervous s7stem as well) as evolving from homogeneous to heterogeneous (specialized and differentiated) entities. Industrialization and urbanization were mechanisms of progress. Vithin this predictable mechanism, the survival principle was held accountable for the poverty, disease, and hardship that accompanied change. For sociology to be a science, it had to be value free. Spencer's evolutionary approach, influenced by Jeremy Bentham's utilitarianism, satisfied this requirement (Haskell, 1977; Pinkus, 1988). Jackson adopted, with some modifications, Spencer's view of evolution to explain the evolution of the nervous system. Spencer's sociological theory, however, was not the milx interpretation of progress (Haskell, 1977). Most serious social thinkers in England and America read Spencer with mingled fascination and horror" and "clung hopefully to a far more 11
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voluntaristic and spiritual view of human affairs. Even Hughlings Jackson often disparaged that the theoretical formulations of the evolutionist did not hold up in the clinic. Those who a~:ept the doctrine of concomitance do not believe that sensations, volitions, ideas, and emotions produce movements or any other physical states. I no more object to the statement that fright makes the heart beat or that mind influences the body at~ clinical conference than I do to the statement that the ~un rises in the east in ordinary talk (Jackson, 1887 !a Taylor, 1958). Nonetheless, this pragmatic methodological approach did allow great progress to be made in amassing objective scientific data" to increase understanding of the nervous system. It was not in isolation, however, from the dominant political and social trends of the time. It was, in fact, intrinsically related to it (Harrington, 1987; Graham, 1979). This process of objectifying facts and separating psychological and moral aspects out of the neurosciences was part of a broader effort by both philosophers and scientists to divorce science and values. There are two opposing views about the separation of science and values during this time period. One asserts that ethics, defined as an academic branch of philosophy, had very little impact on science (Toulmin, 1979). The other, defining ethics as "the principles and conduct of an individual or group" (Graham, 1979) provides many examples to show a multiplicity of connections between science and ethics. In spite of this disagreement both views recognize that from approximately 1840 onward, ethics, as an academic discipline, became a theoretical enterprise. 12
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It was in 1839 that philosopher Yilliam Whewell, elected to the Knightbridge Chair of Casuistic Divinity at Cambridge, changed his title to Professor of Moral Philosophy. Long practicing in the casuistic tradition which centered on the rhetorical solution to specific case problems, moral philosophers like Whewell and his successor Henry Sedgwick, took up the task of framing uniform, consistent moral theories (Jonsen, Toulmin, 19_88; Toulmin, 1988). In the aim of theory construction, only those instances of -morality which furthered theory development were deemed important. This divorce of philosophy from practical matters actually dominated the field of ethics until quite recently. For approximately 100 years, the work-a-day problems of scientists were not within the sphere of interest of academic philosophers who studied ethics (Jonsen, Toulmin, 1988; Toulmin,. 1979; Graham, 1979). This stress on objectivity in science opened possibilities for ethical abuse. Roberts Bartholow, M.D. published an article entitled "Experimental Investigations into the Functions of the Human Brain" (Bartholow, 1874; Clark, Dewhurst, 1974; Churchland, 1986). Paralleling David Ferrier's experimental work on monkeys, Bartholow, an American physician from Cincinnati, conducted electrical stimulation studies on a housemaid named Mary Rafferty. Hospitalized for a cancer of the skull that had eroded the skin and bone and left parts of her brain exposed, Mary was enlisted, while in the hospital to take part in five successive experiments in which Bartholow inserted electrodes deep into her brain, 13
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observed and recorded the resulting focal convulsions, painful sensations, twitchings and on one occasion coma and partial paralysis. His final observations were derived from an autopsy of her deceased brain. Apparently severely censured for this, Bartholow published a letter of explanation in The British Medical Journal. He hoped that it would ease the criticism against him. David Ferrier, acknowledging it, commented on the data Bartholow obtained: mtatever opinion may be entertained as to their propriety, they furnish facts of great interest in relation to the physiology of the brain .... the results are quite in accordance with what one would have reason to expect from irritation in this region ... (Hays, 1874). Ferrier's account, in fact, is as chilling as Bartholow's experiment. Owing to the depth of penetration of the needles, there is reason to believe that the stimulation reached the cerebral centers of the tactile nerves .... This would account for the tingling and painful sensations experienced in the extremities of the opposite side. Of further interest is the occurrence of epileptic convulsions from general diffusion of the irritation when the currents were intensified. Evidently pleased that Bartholow's experiment distinctly bore 011t "the anatomical and physiological homology of the brain of man with that of the monkey and lower animals, Ferrier took pleasure, in justice to Professor Bartholow in referring readers to his letter "which (was) likely to disarm any criticism (Hays, 1874). Bartholow's letter essentially was a disclaimer for his mistaken judgement that "small insulated needle electrodes could 14
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be introduced without injury into the cerebral substance. Having regretfully shown this to be false, he felt, if it were done again it would be "criminal." Yet, Bartholow clarified that Mary died from her disease, not h.11. experimental insults and that she consented" to have the experiment performed. Further research into this incident and Bartholow's ultimate censure will clearly shed light on clinical ethics in the 1870s. It is obvious from Ferrier's remarks, however, that the facts accumulated, advanced knowledge and within his utilitarian framework, could excuse Bartholow's behavior (Bartholow, 1874). Ferrier armed with this objective sci~nce continued to conduct a meticulous series of experiments which identified specific areas of the cerebrum with observed sensory and motor functions. His work and others, by the close of the century, had documented the main cortical centers for motor functions and the various sensory modalities in mammals. It has been considered classic in the mainstream of the neurosciences. The practical consequences of the scientific doctrine of cerebral localization, moreover, have been recognized as providing the groundwork for neurological surgery, which gained status as a separate profession by 1920 (Pinkus, 1984; French, 1986). This "progress" was not unchallenged. The Doctrine of Eguipotentiality. a theory espoused by the influential Jean Pierre Flourens, 1794-1867, was in direct opposition to the localization theory (Flourens, 1846). Flourens and others collected experimental evidence which suggested that any intact cortical 15 ~i
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area could execute the functions of other parts of the cortex. Ferrier, in fact, confronted F.L. Goltz, 1834-1902, leading proponent of the equipotentiality doctrine at the International Medical Congress of 1881. Newspapers publicized the event and described Ferrier's work, which won scientific acclaim, in detail. This broad publicity led to Ferrier's arrest and trial by the antivivisection league! Even though the trial was short and Ferrier was vindicated, the scientific community was stunned that a scientist of such high stature could come under legal scrutiny (Clark, Dewhurst, 1974; French, 1975). The antivivisection movement, responsible for Ferrier's arrest, greatly impeded the progress of experimental medicine in England (French, 1975). It was the ringleader of a complex network of organizations opposed to the scientific .revolution in late nineteenth century medicine, and to the growing social power of doctors. In addition to antivivisection, the coalition included antivaccination, antilicensure, antibacteriology, medical sectarianism, occultism and spiritualism and antipremature burial. Each of these movements held strong moral and religious beliefs which put them at odds with the values of science (Pernick, 1986). By 1890, however, the growing prestige of the medical profession and its perceived value by society combatted these objections (French, 1975~ Pernick, 1986). These individual organizations also existed in the United States, but did not form a strong political organization and was not as obstructionist as in England (Pernick, 1986). 16
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NEURAL TRANSPLANTATION 1909-1917; AT.T. ROADS LEAD TO CHICAGO Vhile the major research questions which dominated the neural sciences in the late nineteenth century were concerned with mapping local areas of the brain, aspects of Flouren's equipotentiality doctrine lived on in experimental medicine and the study of the vitality and degeneration" of nervous tissue. This research agenda was intricately tied to the development of neural tissue transplantations. In 1906 Camillo Golgi and Santiago Ramon y Cajal shared the sixth Nobel Prize in medicine. Golgi developed the histological silver impregnation methods that allowed visualization of the whole neuron: the cell body, the dendrites and the axon. Cajal identified some of the key conceptual insights and much of the empirical support for the neuron doctrine: the principle that the nervous system is made up of discrete signaling elements, the neurons (Cajal, 1928; Kandel, Schwartz, 1981). While close chronologically to the "localizers" of the 1870s and 1880s, these new experimentalists started from a very different perspective: the individual cell. As such, their work enabled them to view the nervous system in terms of a finer level of specificity; one which current neuroscientists readily identify with. Professor Bjorklund, a Swedish neuroscientist who recently has contributed to the basic understanding of neural fetal transplantation, observed that cell properties such as: Trophism, tropism, guidance, specificity and neuralglial interaction were important points of reference for researchers. By the end of the nineteenth century and the early part of this century neuroscientists were certainly 17
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very open minded about the plasticity of nervous tissue and the modifiability of the neuron, its shape and its connectivity. It is relatively recently that we have come back to a similar open-mindedness in the way we experimentally approach these problems (Bjorklund, 1985). Bjorklund's comment actually captures the "spirit of the age. Looking back from the vantage point of the present, wrote historian Geoffrey Barraclough in 1967: Ve can see that the years between 1890, when Bismark withdrew from the political scene, and 1961, when Kennedy took up office as President of the Unites States, were a watershed between two ages. On one side lies the contemporary era, which is still at its beginning, on th~ other there str.etches back the long vista of modern" history with i'ts three familiar peaks, the Renaissance, the Enlightenment and the French Reolution .... It was then that the forces took shape which have molded the contemporary world (Barraclough, 1967). Within this time span, the years 1890-1917 are singled out as the decades when this "decisive boundary in cultural history" first became evident. Talcctt Parsons observed of .these years that "a revolution of such magnitude in the prevailing empirical interpretations of human society is hardly to be found occurring within the short space of a generation unless one goes back to the sixteenth century" (Parsons, 1950). He attributed the change to a convergence of two major philosophical traditions: idealism and positivism. Richard Hofstadter regarded the nineties as a traumatic decade of psychic crisis for Americans. He treated the years 1890 to World War I as the "decisive accommodation of social thought to Darwinian Theory" (Haskell, 1977). And H. Stuart Hughes both recognized and described a "new styLe of thought" which he chronicled as developing from 1890-1930. He characterized it as "a result of a revolt against positivism: 18
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specifically the positivism espoused by Herbert Spencer (Hughes, 1958). It was during this time period when the boundaries and concept~ for the social sciences in their present academic, specialized form were crystallized. Two decades of unprecedented urban-industrial growth witnessed a profound and rapid alteration in material life. This was also the era in which medical education and the profession of medicine generally came of age in America. Abraham Flexner's famed Camegie Report was publisbed in 1910 and by 1920, the new standards for science-based, four year medical curriculum were well on their way to being institutionalized (Starr, 1982; St~vens, 1973). Given this larger historical context, it is in a sense convenient" that the dates of 1890 and 1917 mark the time when the first" and last of the first spate of American publications on mammalian transplantation were written. By examining them with an eye to this intellectual watershed" they contribute not only to an understanding of neural transplantation but to the intellectual history of medicine as well. W. Gilman Thompson's contribution (Thompson, 1890)1s key to understanding the conceptual accommodation which took place in the neurosciences during these 20 years. He appears to be a transitional figure in the early neural transplantation work. That is, while he, S.W. Ranson and Elizabeth Hopkins DuM were contemporaries, they were, in terms of their scientific methodology, in different centuries. Thompson, as Director of the 19
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Loomis Laboratory rigorously supported the development of clinical research along with laboratory investigation as the basis of scientific medical discovery" (Kaufman, 1984). He wrote books on dietetics and practical therapeutics, industrial hygiena and sanitation. He was American-trained" and demonstrated a pragmatic, clear-cut approach to problems. His foray into neural transplantation, however, appears to have been the pursuit of an isolated idea. His reference to "the great scientific interest in demonstrating the relative vitality of different tissues and the histological changes which accompany degenerative processes" reflects concerns raised later by Ranson and Dunn. Yet, his reference to Darwin's laws of atrophy and final disappearance of disused organs" and to cerobral localization in lower animals" suggest an acceptance of a knowledge base which was specifically criticized by Ranson (Ranson, 1903). Thompson, for example, disavowed entertaining any thought of the functional significance of his transplantation experiment. Yet, he paradoxically also accepted as a given, that "there is no doubt that in manp as well as in lower animals, nerve fibers may reunite when sutured even after secondary degeneration has occurred and they exhibit restoration of function" (Thompson, 1890). His research was not linked to any integrated experimental effort nor did it benefit from the new findings of embryologists, concerning appropriate animal models for the study of human anatomy. Thompson grafted brain tissue from one side of a dog's brain to another and from a 20
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dog to a cat. It did, however, serve as a bridge to introduce neural grafting as a technique that could be refined in the hands of others. In bold contrast to Thompson's isolated and somewhat idiosyncratic attempt at nerve grafting, is the combined and coordinated effort documented by Alice Hamilton, M.D., 1869-1970, S. ~alter Ranson, M.D., Ph.D., 1880-1942, J.B. Watson, Ph.D., 1878-1958, and Elizabeth Hopkins Dunn. These four individuals actually represent a curious mix of talents. One might safely conjecture that if it were not for H.H. Donaldson, 1857-1938, they may not have added their genius to transplantation work. In 1895, when his classic reference book, The Growth of the Brain; A Study of the Nervous System in Relation to Education (Donaldson, 1895) was published, Donaldson was co~sidered one of the world's foremost authorities on the brain (Kaufman, 1984). His long and distinguished career, which centered on studying the development of the human brain from birth to maturity, played an indirect yet pivotal role in promoting basic research on transplantation of mammalian tissue; for it represented a new professional standard for conducting brain research. From 18921906, Donaldson was on the Neurology faculty at the University of Chicago and head of the Hull Laboratory. In 1906, he assumed Directorship of the Vistar Institute of Anatomy and Biology. A post which he occupied until 1936. Educated both at prestigious American institutions and in Europe, he represents the values of a new type of mentor in scientific medicine. During his 14 years 21
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at Chicago, Hamilton, Ranson, Yatson and Dunn each worked under Donaldson's direction and contributed to his overall research agenda. This agenda was to study "post-natal ,Jrowth in terms of cell multiplication and cell structure, with its many subsidiary problems" (Conklin, 1939). Donaldson's method of directing research work highlighted what was expected of young, research physicians. No investigator is ever asked to do anything which is not for his individual and scientific welfare. For the most part, those who come to the Institute are in the early stages of their scientific work and do not bring their problems with them. It is for us, therefore, to suggest one ... As an aid in obtaining orderly data which will interlock, the papers of the younger men have been in every case read critically by some member of the staff familiar with the field, with the new observations brought into relation with those previously published .... Such criticism assists the younger writer in several ways and also makes it possible to tie together the results of consecutive studies in a manner that gives cumulative v~lue (Conklin, 1939). The animal which Donaldson chose as "the best available mammal for laboratory work on problems of growth" was the white rat. I selected the albino rat as the animal with which to work. It was found that the nervous system of the rat grows in the same manner as that of man--only some thirty times as fast. Further, the rat of three years may be regarded as equivalent in age to a man of ninety years, and this equivalence holds through all portions of the span of life, from birth to maturity. By the use of the equivalent ages, observations on the nervous system of the rat can be transferred to man and tested. The results so obtained show a satisfactory agreement and indicate that the rat may be used for further studies in this field. (Conklin, 1939: Donaldson, 1924). Donaldson's book The Rat; Data and Reference Tables for the Albino Rat and the Norway Rat was first published in 1915 and 22
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revised in 1924. It is largely because of this work that the albino rat gained prominence as the laboratory mammal generally and why early transplant work carried out by Dunn and Ranson met with such success. Alice Hamilton, M.D., 1869-1970, like Thompson, distinguished herself in the field of Industrial Hygiene. She received her M.D. from the University of Michigan in 1893, intemed at Women's and Children's Hospital in Minneapolis during 1894-95. From 1895-1896 she studied at the Universities of Leipzig and Munich and then at Johns H~pkins. She spent but two years in Chicago: 1898-1900 (Kaufman, 1984). H~r 1891 publication has been "buried in the archives" along with others, until current interest in transplantation revived it. Cited by Ranson as providing a hypothesis to use immature rats in his _1903 experiments, it is given mention here as evidence of the rich experimental milieu Donaldson built up and how his integrated methcd of assigning research topics did lead to cumulative knowledge about a particular topic (Hamilton, 1891). Stephen Walter Ranson (1880-1942) was a dominant contributor to neuroscience. In addition to his popular text Anatomy of the Nervous System (1920, 1923,1934) he is best known for his experimental stereotaxic studies of the function of the hypothalamus. Ranson, however, began his career with questions of regeneration and degeneration of neural tissue (Kaufman, 1984) and pursued this work using transplantation techniques. He received both his M.S. and Ph.D. at the University of Chicago from 1903-23 -. -
PAGE 27
1905. It was at this time that he apparently met and perhaps worked with Dunn in Donaldson's laboratory. His first research concerning regeneration of nervous tissue was published in 1903. Like Thompson, Ranson explicitly disavowed commenting on any functional value of his work in mammals. Ranson, however, offered an explanation. His interest was in documenting only the presence or absence of "new-formed nerve elements" which could be studied "quite apart from the physiological value of these elements." This separation would make it possible to sort out the confusion he found in current literature on regeneration of the spinal cord in mammals caused by a failure to appreciate the difference between "reflex and voluntary movements. Unlike Thompson, Ranson reviewed virtually all published literature on this topic and was critical of those studies which.claimed to document return of function (Ranson, 1903). While it is impossible to document precisely Ranson's intellectual base, it is here suggested that indirectly, reverberations from Gall's crude attempt at localization still sensitized researchers tackling questions of volition. Clearly Jackson's conceptual distinctions provided the framework for study. By 1914, Ranson had conducted two studies which used transplantation as a method to facilitate observation of the behavior of complex types of spinal ganglionic cells. He noted specific and complex changes in these cells. Our own observations confirm those of previous investigators that simple unipolar cells may be transformed under experimental conditions into complex multipolar cells. An additional fact of importance brought out by 24 ~1-
PAGE 28
this investigator is that such multipolar cells can return again to their original simple form (Ranson, 1914). Having documented these complex and inexplicable findings, Rans.,n simply concluded: Just what factors bring this about is here left unmentioned because we have no adequate means for forming a conception of them, and what theorizing has been done--has obscured che question (Rctnson, 1914). Ranson's interest in neurology far exceeded his early experime .'ts in Donaldson's laboratory. In 1920, he published his text, Anatomy of the Ner.~ou~: System. a resource book which underwent 11 editions until it was discontinued in 1961. After his death in 1942, his colleague and friend, S.L. Clark, continued the text, editing and updating six editions. The 1920 version is considered a rare book" in historical collections and was not available for review. However, editions 2 (Ranson,. 1923) which had minor changes from the first edition; 6 (Ranson, 1939); 8 (Ranson, Clark, 1947); 9 (Ranson, Clark, 1953) and 10 (Ranson, Clark, 1959) are here utilized as a means for assessing the types of information considered important enough to teach the younger generation. Also, Ranson's views on consciousness and on the functional significance of neuroscience are documented. One striking feature of the 1923 text is that Cajal's work is used as a gauge against which old, new and uncertain facts conceming the nervous system are compared. Throughout the book, the neurone theory is examined, challenged and updated. This is done as an aside" to the standard references, in small print, and invites the reader to actively engage in ongoing debate. Another 25 ,'-/
PAGE 29
is that there is no reference to Ranson's or anyone else's transplantation experiments. The changes Ranson cited in this 2nd edition of his textbook are instructive in evaluating how he viewed the functional significance of neuroscience. It appeared that as scientific facts merged with possible clinical applications, functional significance developed. In Ranson's words: "brief accounts of twelve clinical cases selected to illustrate the functional significance of various parts of the nervous system were important additions to his revised text. The twelve cases illustrated classic neurological signs and symptoms resulting from specific focal brain leisons. Parkinson's disease was not one of the twelve cases listed, but as early as 1923, Ranson wrote: A great deal of attention has recently b~en given by clinical neurologists to the disturbance of voluntary movement by tremor, rigidity and athetosis, which results from lesions of the corpus striatum. The body seems to contain an important motor center, ... it exerts a steadying influence upon voluntary movements. Conjecturing why this was so, he reviewed the known anatomy and concluded with Cajal's observation that It is known that axons arising in the substantia nigra run into the reticular formation of the mesencephalon, beyond which they cannot be traced (Ranson, 1923). This entry is included in the sixth edition; the eighth also (Ranson, 1939). By 1953 and 1959, when the ninth and tenth editions were published, the entry was substantially updated to account for new data regarding fibers connecting the substantia nigra and the corpus striatum. As to the functional significance of this area of the brain, it was repeated that "very little is 26
PAGE 30
known .. except what may be inferred from the symptoms exhibited by patients in whom the basal ganglia are diseased. Some exhibit the Parkinson syndrome .. (Ranson, Clark, 1959). Recall that the ability to identify neurotransmitters was not developed until 1962. Ranson's views on consciousness suggest an "accommodation" or relaxation of the strict parallel view of mind/body defined under Jackson's concomitance model. In the present state of our knowledge of cortical activity and its relation to consciousness it is the part of wisdom to be very conservative in locating any mental faculty or fraction of our conscious experience in any particular part of the cerebral cortex. Espousing a view which combined both localist and equipotential concepts he observed: The various parts of the cerebral cortex are so intimately linked together by association fibers that when afferent impulses reach a given projection center they must not only activate this center, but be propagated to other parts of the cortex as well. In view of these facts it is best to express the known facts of cortical localization in terms of the relation of particular areas to ~he known projection fiber system (Ranson, 1923). As will be discussed later, these views were also shared by C.S. Sherrington, and have been carried into current discussions by Eccles (Clark, Dewhurst, 1974). Localization of motor and sensory functions, in sum, were accepted. Localization .of consciousness, was clearly not understood, but given the complexity of the brain was at least considered. In this context the few experiments Ranson and Dunn had conducted using transplantation technology indeed seem trivial. Elizabeth Hopkins Dunn received her M.D. from Northwestern 27
PAGE 31
University Women's Medical School in 1894, and was a graduate student at the University of Chicago from 1898-1901. She served as a technical assistant in neurology there from 1901-1903; a research assistant from 1903rl906; and as both an assistant and associate instructor in anatomy until 1909 when she left to take a position in Woodshole Laboratory in Massachusetts (University of Chicago Annual Recister. 1911-1912). As such, she was educated before the Flexner Reforms in medical education, a time when entrance requirements encouraged a variety of students to pursue careers in medicine. Nonetheless, she was a woman in what was fast becoming a "man's world." In this light, her contributions have an added interest (Gash, 1989, personal communication) (Starr, 1982; Stevens, 1973). In her paper entitled, "Primary and Secondaey Findings in a Series of Attempts to Transplant Cerebral Cortex in the Albino Rat," Dunn indicated that her initial experiments were performed in Chicago under Donaldson's suggestions. One may surmise that they were completed at Woodshole, apparently in 1916. She reported unpublished work conducted by S.ll. Ranson, reviewed and confirmed hll important papers on transplantation, which were published in 1909 and 1914. Dunn's work which both confirmed, updated and expanded upon Ranson's experiments demonstrated two basic concepts central to current day neural transplant techniques. The first was that immature neural tissue could be successfully grafted. The second pointed to the importance of using a rich vascular bed to insure graft survival (Dunn, 1917). 28
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Her publication, however, is not only of interest because of its scientific merit. It also provides many clues to understanding how transplantation work fit into the larger research agenda of this time period. Dunn indicated that she collaborated with the leading figures in neurology and psychology and, as was the custom then, made a point to include their names in her research article. In addition to Ranson, who was then probably her peer, she mentioned C.S. Sherrington who visited the Donaldson laboratory in 1904 when Dunn conducted her original experiments. To him she attributed the "warming technique" used so that the newborn rats could be removed from their nest, operated on and returned to be nurtured not eaten. Ranson described this technique in detail in his 1903 paper but did not attribute it to Sherrington. Also, Dunn thanked J .. B. tlatson for growing the strain of rats which she used in her experiments. J.B. tlatson, 1878-1958, was another early member of Donaldson's laboratory. Apparently his early experiments in Donaldson's lab determined that the nervous system of the newborn white rat did not contain a single medullated nerve fiber. However, the increase in the weight of the brain is very rapid during the first few weeks of life, and he attributed this to the growth of medullated fibers. It is of interest to note that the title of his treatise was Animal Education; An Experimental Study on the Psychical Developments of the White Rat Correlated with the Growth of its Nervous System (Watson, 1903). Watson's contributions were not, however, to be in 29
PAGE 33
neurology. He is best known for the major impact his paper on behavioralism (Yatson, 1913) had on the course of American psychology. Reacting against the tradition of his time which promoted introspective study of conscious experience as the province of psychology, Vatson boldly proposed that one could study psychology without making assertions about consciousness. Instead, he centered on the seudy of adjustive processes: the various muscular movements and glandular secretions of animals and infants. Behavior, Yatson observed, was public; consciousness was private. It was his contention that science should deal with public facts (Hilgard, Atkinson, 1967). A competing view in psychology at the time was the Gestalt theory. It held that our mental processes were organized around patterns of experiences and stimuli. Moreover, the whole picture, or Gestalt, was asserted to be different from the sum of its parts; it consisted of parts in relationship. This view was in open opposition to Vatson's behavioralism. Not wishing to give up a kind of free introspection, Gestalt psychologists stressed the importance of perception and interpretation. These interpretations were spoken of as forms of cognitive theory and were contrastod with stimulus-response interpretations of Yatson (Hilgard, Atkinson, 1967). Dunn, Ranson and Yatson conducted their research during the precise historical period in which the emerging specialties of neurology and psychology were becoming entrenched institutionally as separate academic traditions (Haskell, 1977). Given their 30 -,,,,,-<. .... / -
PAGE 34
common background in Donaldson's laboratory, they each ascribed to the same objective observational method. Ranson admitted that concepts were unavailable to him to explain the structural changes he saw in the cells. He accepted and described the changes and sought to understand the "why" in physiological terms (Langley, 1972). llatson could label h1i. unknown consciousness and opted to not try to define it. Ranson clearly acknowledged this behavioralist perspective but was never quite convinced that consciousness was a concept inappropriate for study by the neuroscientist. As the century has progressed, it has become more difficult to appreciate this common base. Neural transplant technology in mammals, in sum, played a major role in understanding the nervous system, at a very basic level: the cell. It was a technology utilized by.key researchers in the neuroscience community to provide data for the broader questions they pursued. Neurologists, however, were not the only members of the medical profession interested in transplants. TRAN$PIANTATION AND THE EARLY 'ljlENTIETH CENTQRY;NERVE GRAFrING, EMBRYO CHICKEN HF.ARTS AND IMMORTAL CEI.i LINES Alexis Carrel, M.D., 1873-1944, gifted and creative surgeon, is not usually included in discussions of the history of neuroscience. Yet, he too spent two years, 1904-1906, with the physiology faculty at the University of Chicago where he commenced laboratory experiments in transplantation and tissue culture. There is no direct evidence to suggest that Carrel worked with Donaldson, Ranson or Dunn during the years he held the position of 31
PAGE 35
Professor of Anatomy at the University of L"hicago. Yet, the national acclaim his work received in 1912, with the award of the Nobel Prize for physiology and medicine, and the continued coverage of his tissue culture work in the popular press, suggest that both he and his work were known to these contemporary neuroscientists. Thus, Carrel is in a pivotal position to explain public and scientific attitudes and approaches to transplantation in the first decades of the twentieth century. Carrel had common intellectual and scientific ties with both Dunn and Ranson. All three were influenced by the tissue culture techniques of Ross G. Harrison, 1870-1959, of Yale. The ways in which they incorporated this information into their own work illustrates the range of uses" transplantation technology had during this time. Harrison developed a method .to study the mechanism by which embryonic nerve fibers developed and connected to its various parts. At the time, some embryologists thought that fibers grew to varying lengths from individual nerve cells in the brain, spinal cord, or outlying ganglion. Others maintained that nerve fibe~s were formed from short lengths produced by local cells and then connected end to end. Harrison cut out a section of the spinal cord of a chick embryo and placed it in a clear drop of clotted lymph. He then placed this in a hollowed out glass microscope slide so as to be able to watch the nerve fiber grow, unobscured by other tissues. He took serial photographs daily of nerve fibers sprouting from nerve cells and growing into the clotted lymph (Edwards, 1974).
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Carrel had left the University of Chicago in 1906 to pursue his research within the well endowed and newly built Rockefeller Institute. He wanted to learn Harrison's technique to use in his laboratory and sent Montros T. Burrows, his young research assistant at the Institute, to spend several months with Harrison in 1910. Burrows not only learned the technique, but he improved upon it by using bl~~d plasma instead of lymph. Kore easily accessed than lymph, it formed a mesh when it clotted and still allowed the cells to grow unhampered. He published his findings in a 1912 paper which both Ranson and Dunn cited in their experiments (Dunn, 1917; Ranson, 1914). Dunn, in particular, viewed his accomplishments as support for the possibility of successful nerve grafts. Carrel utilized it to continue his experiments with malignant cancer cells, thyroid and kidney cultures from cat and dog tissue. Carrel's work with cultures of living tissue at the Rockefeller Institute attracted wide public attention from 19061917. He cited two reasons for attempting to grow tissues outside the body. One was to study the mechanism by which wounds heal, an interest which both Ranson and Dunn also expressed (Ranson, 1909; Dunn 1917). He hoped that by removing cells of skin, connective tissue, blood vessels and nerves from the body and observing their growth, he could discover how much of the healing process was carried on by the cells themselves as opposed to the organizing ability of the body. His second reason for culturing living tissue was more 33
PAGE 37
aabitiowa. Prompted by his vork in a}!tery grafting and organ transplantation, Carrel openly expressed a hope of keeping human organs and tissues alive and in storage to be used as replacement parts (Carrel, 1906). In 1910 he published a report that he had grown several kinds of highly organized adult tissue. He also presented to the Societe de Biologie of Paris findings which were said to be primary, secondary and tertiary cultures of thyroid glands Both the paper and the presentation were harshly criticized: his cultures were read as connective tissue not thyroid cells. It was this incident which led Carrel to covet his now famous embryonic chicken heart culture, which it has been claimed was kept alive through many generations (Hendrick, 1913; Pemick, 1986). Scientists, like Dunn and Ranson, thought of the tissue culture technique as a new way of studying life processes, and perhaps enhancing the success of neural grafting. Newspaper accounts, however, fascinated with Carrel's views, discu..ssed tissue culture as evidence of immortality, described and showed photographs of living cells multiplying and growing in glass tubes. These reports stressed that the cells existed long after the death of the animal from which they were taken. For neurologists, Carrel's organ separation and tr~plant experiments strongly reinforced notions that the brain was the locus of the inte1rative activity that constituted individual life (Pernick, 1986). Carrel, in sum, represented a scientist not bound by the 34 -'. (:
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methodological parallelism incorporated into academic neuroscience in the United States. Nobel prize aside, his belief in culturing "immortal" cell lines and in miraculous cures, combined with his flamboyant sense of showmanship set him outside the mainstream of American science. His somewhat unorthodox popularizing of transplantation techniques may have caused a conservative experimentalist like &anson to downplay this aspect of his work, but this would have to be documented with primary historical material. In addition, because of Carrel's questionable collaboration with the Nazi's during World War II, his career and accomplishments have been somewhat tainted by later generations also. CORCIJJSIQR; A MERGING OF THE THEORETICAL VITH THE PRACTICAL In contrast to the lag of experimental work .in neural transplantation after 1917 is the rapid and steady increase in papers published in this area since 1970. "It is illustrative, writes Gash, "that more papers on mamm&lian CNS grafts were published in 1980 alone than were published in the first 60 years (1890-1950) of work in this area" (see Figure #3) (Gash, 1984). Reasons for this progress were discussed in the introductory section of this paper. It is cited here to emphasize that these developments raise again questions of philosophical import for the neuroscientist. At the most abstract level, neural grafting has directed attention again to the perennial questions of mind/body relationships which were debated with such vigor from 1850-1890. 35
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26 2, 22 20 II 16 ,. 12 10 I 6 2 o..,._ __ _...___..~_ ................... ..AU__.,.....,......,.,,....MA.I& 1190 1900 1910 1920 1930 1940 1950 1960 1970 1910 .YEARS Figure 3. This graph shows the number of papers published each year from 1890 to 1980 on experiments utilizing transplantation procedures involving CNS neurons of mammals. Compiled from Index Medicus and other sources. Gash, 1984
PAGE 40
The debates, of course, actually date to the time of Aristotle; for physicians have always strived to define the substantial nature of the mind. In today's context, however, these questions are posed by some molecular biologists who ponder the overall significance of their field to the study of neurobiology: These new approaches have accelerated the growth of neurobiology .. and two unanticipated consequences have changed the ways in which clinical researchers and practitioners can now view the findings that came from basic science. The first consequence is a new unity, a greater coherence, in biology as a whole, as studies move from the level of the cell to that of the molecule .. the second consequence of our increased knowledge .. [is that a]s a science becomes more powerful, it becomes more ambitious-it becomes bolder ... Many molecular biologists now frankly admit the ultimate object of their interest is not simply the system with which they work. It is not simply lamda, the T4 phages, or E, coli. It is not even C.elegans, Drosophila, or Aplysia. It is human biology. And some biological researchers as so bold as to see their ultimate interest as the function of the human mind (Kandel, 1987, as quoted in Schaffner, 1988). Eric Kandel, a Professor of Physiology and Psychiatry at the College of Physicians and Surgeons, Columbia University, is author of the above quote. He asserts that this "optimism is not new to neural science, ... but it is more realistic than it was before. He points to an esteemed colleague's "prophetic insight" as providing the groundwork for such a view. The modern era in neural science began about 30 years ago. In 1953, Sir John Eccles (who won the Nobel Prize in Physiology ... ) reviewed results based on the first intracellular recordings from single nerve and muscle cells in a book he modestly entitled The Neurophysiological Basis 2.f_.tllng .... As time went on, many of us have returned to this marvelous book .. (it) pointed the field in the right direction (Kandel, 1981). In that book, Eccles discussed neurophysiology. His topics began 36
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with reactions of the single nerve or muscle fiber: continued to discuss the reactions of the cerebral cortex and concluded with his ideas regarding the relationship of the brain to the mind. That relationship, Eccles asserted, was dualistic and interactionist. He stated that 11!. was following the lead of C.S. Sherrington who posed similar views in his book Man and His Nature (Sherrington, 1951). Eccles, like Sherrington, utilized~ scientific methodology to formulate testable hypotheses to prove his stance (Eccles, 1979). In 1977, he expanded his views in a book coauthored with philosopher Karl Popper entitled, The Self and Its Brain: An Argument for Interactionism (Popper, 1977). He has reaffirmed his dualistic views in a recent neuroscience textbook (McGreer, Eccles, McGreer, 1987). These in turn have been c~iticized by philosopher T. Honderich (Honderich, 1988). Tristram Engelhardt, M.D., Ph.D., a philosopher, reviewed Eccles and Popper's 1977 book and held firm to Jackson's nineteenth century concepts. He characterized Eccles interactionist view of mind/body as representing a "Pre-Jacksonian" stance and compared it to the theories for eguipotentiality in the brain espoused by MarieJeanes Pierre Flourens (Flourens, 1845). He surmised that by returning to Flouren's model, Eccles abandoned the search for physiological unities by invoking psychological causes. Repeating classic philosophical reasoning, Engelhardt did not object to the interactionist stance on metaphysical grounds. He stressed again that Jackson's rejection of interactionism was methodological and 37 A--c
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that his proposal was to test out the feasibility of the neural sciences without any attempt at reduction of the mental to the physical and without a metaphysics of an independent mind. The feasibility, purported Engelhardt, was still patent. At this juncture, he advised against a pursuit of interaction for it would appear to entail an excessive conceptual cost without sufficient warrant (Engelhardt, 1979). Engelhardt wrote in the late 1970s, a time when some philosophers began to envisage a scientific futu~e for the traditional problems in the philosophy of mind" (Churchland, 1988). Philosophy had traditionally been regarded as an a prior discipline whose truths were accessible by non-empirical methods, and whose discoveries supposedly laid a prior foundations for any science. Two philosophers, Y.V. Quine and Paul Feyerabend, independently undermined this view by asserting that philosophical knowledge, like scientific knowledge was the result of empirical discoveries and theoretical progress, hence, it was open to revision (Churchland, 1988). Vithin this new conceptual, philosophical framework, Engelhardt's traditional discussion of the mind-body problem has been augmented by investigation into a different set of problems. These include the relationships between experimental psychology and neuroscience; the assessment of strategies to understand the nature of perception, cognition, reasoning, consciousness and language use. They also include serious consideration of whether or not psychology will reduce to neuroscience (Churchland, 1988). 38 .4.,
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Patricia Churchland's book entitled Neurophilosopby exemplifies this new trend. By combining philosophy, neuros~ience and history, she sets the stage for a description of what a philosophical reduction of the mental to the physical would entail. She suggests that as science advances some fundamental principles or entities such as beliefs and "desires"--currently the purview of folk psychology may be replaced by explanation at the molecular level (Churchland, 1986). One is tempted to compare Jackson's bafflement at the clinical observation that "fright makes the heart beat" with subsequent knowledge of the autonomic nervous system (Langley, 1972); or the nineteenth century queries regarding volitional movement and with recent work in muscle contraction and free energy transduction (Eisenberg, 1985). These are both instances of successful reductions of psy~hological concepts to biochemical explanations. As experimental evidence accumulates in the neurosciences during the past 10 years, however, it continues to confirm how complex the nervous system is. Schaffner, in fact, in an intricately detailed analysis of "Reduction and the Neurobiology of Mind" (Schaffner, 1988) examined the nature of intertheoretic reduction in general and paid particular attention to reduction involving the "mental" to the "physical." He chronicled and revised philosophical definitions of reduction, discussed major advances in molecular neurobiology and concluded, "such a reduction is clearly fragmentary and exceedingly complex" (Schaffner, 1988). Echoing the continued point counterpoint 39
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between holistic and ocalist views (Gardner, 1985), Schaffner speaks of partial reductions" and reasons that "it would seem that for the present and foreseeable future, neurobiology will not be a fully reducible science (Schaffner, 1988). These new views of reduction are not unanimously applauded. Howard Gardner recognizes that neuroscience is still a young field in the process of defining, rather than resolving many principles. In the tradition of the Gestalt psychologists, he regards All reductionist arguments (weak and strong) as untenable. Upholdfng the perspective of cognitive science, he argues that: It is not possible to enter into the nervous system as a disinterested observer who is simply chronicling the facts .... Both the topics studied, and the ways in which they are studied, will reflect implicit theories about what perceptions, cognition, or language are; what is important in each; and how each of these processes occur (Gardner, 1985). These more general theoretical issues regarding the relationship between mind and brain, in sum, remain contentious. Specific advances in neural tissue transplantation, however, have engaged both philosophers and neuroscientists in issues which have a more immediate impact and demand solutions. Philosophers familiar with ethics in health care generally have discussed the issues using the principles now familiar to medical ethics: the "respect for autonomy and a balancing of harms and benefits that gives priorities to those most effected" (Caplan, 1987; Mahowald, 1986). Vithin this framework, they conclude that the use of fetal neural tissue for research or therapy is justified in certain circumstances. Thus, they provide guidelines 40
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and "wedges" decisionmakers could use to permit transplantation and yet limit some aspects of its technological application. Neuroscientists, wary of the rapid application of their research efforts, have also entered this ethical debate. John Sladek, Ph.D., Killian and Caroline Schmitt, Professor and Chairman of Neurobiology/Anatomy, University of Rochester School of Medicine & Dentistry and Ira Shoulson, Professor of Neurology, Medicine & Pharmacology, Director of Unit of Movement and Inherited Neurologic Disorders, also in Rochester, cite the rise and fall of adrenal medulla transplant efforts and stress that These disappointing developments and the public attention accorded to neural grafting prompt a critical reevaluation of this experimental procedure in humans as well as consideration of some basic medical values and scientific justifications (Sladek, 1988). The questions they address fall within the ~road category of research ethics and could profit from careful scrutiny using methods outlined by previous investigations (Levine, 1984; Belmont Report, 1974). They include criticism of the rapid clinical application of adrenal medullary autograft studies in PD patients. Clearly, Sladek and Shoulson feel publication of findings based on only 2 patients in the prestigious NEJM did not constitute sufficient evidence for clinical application. They cited statistics which indicate that the postoperative mortality rates of the procedure may exceed the expected annual mortality from natural causes, as reasons for caution. Raising a perennial problem posed in the practice of surgical innovation generally (Bosk, 1979), they also question the justification of 41
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investigators operating on two or three patients to gain a firsthand experience and facility with of the unproven research procedure. Citing an isolated case report of surgical technique performed for Parkinson's disease in 1940 which underwent a similar pattern of application, hope and within two years complete absolescence, they offer their tacit ethical wisdom and acknowledge that "considerable time is needed for clinical evaluation and early judgments can be flawed." Using detailed scientific knowledge of transplantation, Sladek and Shoulson also review specific unknown factors which could confound interpretation of operative results. Thus, they question why the primate model available to test out some of the unknowns was overlooked. "Has the animal rights lobby intimidated investigators to the point where they are being un~uly pressured to carry out animal research on humans?" They also entertain the possibility of using other donor sources including cells "produced from an immortalized cell line, perhaps of human embryonic origin." In conclusion, these authors contend that as a society we have not yet had sufficient time to fully explore and understand the many issues attendant to embryonic cell grafting for neurodegenerative and other disorders. Perhaps, they reason, we could benefit from more patience rather than more patients" (Sladek, Shoulson, 1988). Alan Fine, Assistant Professor of Physiology and Biophysics, Faculty of Medicine, Dahousie University, Halifax, Novo Scotia provides another perspective. He also reviews the 42
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scientific grounds for neural grafting and points to the data indicating that fetal tissue would be the most promising source of graft material. He then addresses the abortion question and the perceived social barriers to the use of fetal tissue in grafting. After reviewing current legal and moral guidelines, he essentially agrees with the conclusions elicited from the NIH Review Board (Biolaw, 1988) and those published by medical ethicists (Caplan, 1987; Mahowald, 1986). "Fetal tissue transplantation for treatment of Parkinson's disease, as described here," reports Fine, "poses no risk of eroding these barriers" (Fine, 1988). While it is instructive and impressive to attend to the specific issues discussed by these authors, it is also important, by way of conclusion to this paper, to recognize the blending of ethical and scientific concerns evident in their w~rk and that of other neuroscientists (Gash, 1988; Joyne, 1988). Consider, by way of comparison Ferrier's detached utilitarian assessment of Dr. Bartholow's research results. This represented the dominant conceptual framework for scientific investigation during his day. This framework was not unique to nineteenth century Britain. Preliminary work by Rothman, in fact, confirms allegations made by Beecher (Beecher, 1966) and suggests that similar values, albeit for different reasons, were evident in the pursuit of scientificmedical facts in the U.S. from 1945-1960s (Rothman, 1987). The current awareness and integration of a variety of philosophical concerns in the day-to-day practice and publications of neuroscientists, from abstract discussions of mind/body 43
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relations to tacit knowledge of research ethics, represents a signific~nt shift in scientific thought. Advances in both philosophy and science, in sum, have brought us to this particular historical juncture in which the task at hand is to devise policies to direct or discourage the continued development of specific technological advances. In this sense, the issues specific to neural transp,lantation and Parkinson's disease are similar to those which prompted the rise of the bioethics profession in general (Rothman, 1987; Vertz, 1979). Yet, as this review has shown, questions having to do with the brain and its complexities have always demanded attention to moral, psychological and scientific realms of knowledge. In the nineteenth cen~ury and until quite recently, it was the pragmatic decision of neuroscientists and philosophers to separate these bodies of knowledge. Current practice not only blends psychological and neurological knowledge, but has included a specific type of moral questioning as well (Toulmin, 1988). Peter Medawar, in analyzing The Limits of Science (Medawar, 1984) distinguishes "between questions of the kind science can answer and questions belonging to some other world of discourse He concludes that it is "logically outside the competence of science to answer questions having to do with first and last things. He then defines the types of questions science is capable of answering and asks: is there a limit to this pursuit? Stating hll view of progress, he contends that In the world of science anything that is possible in prinicple can be done if the intention to do it is 44
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sufficiently resolute and long sustained. This places upon scientists a moral obligation which, considered as a profession, they are only now beginning to grapple with (Medawar, 1984). Medawar also recognizes the societal context in which science exists and states from our political masters it calls for a degree of wisdom, scientific understanding, political effectiveness, world sense and goodwill that no administration in any country has yet been able to master. It must be kept in mind, however, that Medawar's statement is philosophical. As such, it represents the construction an ideal to strive for. 45 r! < ,_:
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