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J7ournal ofMedical Ethics 1998;24:118-122 J Med Ethics: first published as 10.1136/jme.24.2.118 on 1 April 1998. Downloaded from

The - quiddity: ethical issues in the use ofhuman brain tissue for therapeutic and scientific purposes Larry Burd, Jennifer M Gregory and Jacob Kerbeshian University ofNorth Dakota, USA

Abstract understanding the unique construct of brain The use ofhuman brain tissue in activity which we call "the mind". This term, "the research is increasing. Recent developments include mind", is the conceptual vehicle used to commu- transplanting neural tissue, growing or maintaining nicate many of the brain activities which have yet neural tissue in laboratories and using surgically defied either anatomical or functional localization. removed tissuefor experimentation. Also, it is likely In some people with substantial amounts of miss- that in thefuture there will be attempts at partial or ing brain tissue all of these activities occur. Other complete brain transplants. A discussion of the ethical people with apparently normal demon- issues of using brain tissuefor research and strate very few of these activities. Although the brain transplantation has been organized around role ofindividual parts ofthe brain remains poorly nine broadly defined topic areas. Criteria for human understood neuroscience seems posed to make use remarkable progress in the near future. A recent brain tissue transplantation and laboratory of copyright. brain tissue are proposed. development in clinical neuroscience has been the (Journal ofMedical Ethics 1998;24:118-122) isolation and laboratory growth ofbrain tissue Keywords: Brain transplantation; neuroscience; person- lines in laboratories around the world.4 These hood; life; ethics; brain; mind efforts at the cellular level and the whole brain or total body transplants in animals completed more than three decades ago by White and colleagues In a previous issue of the journal, Dr Gillon's edi- seem certain to be the focus of increasing empha-http://jme.bmj.com/ torial provided a framework and commentary as a sis from neuroscientists in the future. These companion piece to an article by Dr Northoff on strategies offer attractive methodologies for re- ethical issues of brain transplantation.' 2 These searchers and clinicians who seek to ameliorate articles provided an important first step for the sequelae of human central discussion of the philosophical and ethical issues disease and dysfunction."8 In contrast to the suc- surrounding brain transplantation. In this paper cess in animals of head transplants, the current we wish to add to this ongoing discussion and to science base suggests that mature cerebral tissue on September 24, 2021 by guest. Protected describe several additional relevant areas in this in large blocks cannot be homotransplanted into discussion. These issues relate to development of mature brains.7 8 These efforts at the cellular level the mind-brain duality, personhood, and self- on the one hand and at the level of whole brain identity. The 1990s have been designated as the transplants (limited to animals to date) on the "" to recognize both the other, give rise to nine important ethical, social, tremendous progress that has been made in the and scientific questions which are the focus of this basic and clinical and to call atten- discussion: tion to the work yet to be done.3 Late into this decade important advances have revealed insights 1 Is it possible to grow brain tissue without the into the molecular basis of several neurological occurrence of corresponding mind (mental) disorders, for example, the diagnosis of Hunting- activities? ton's and Fragile X Syndrome. Impressive 2 If activity is present in this tissue, does it advances have accompanied these basic science support a mind-brain unit and as a result generate efforts in the understanding of functioning of the , sensations, or other internally gener- . stud- ated brain activity? ies have substantially enhanced the scientific 3 Should developmental experience be a criterion understanding of brain organization. However, for the brain-mind unit to have the qualities of a relatively little parallel progress has been made in person? Burd, Gregory, Kerbeshian 119 J Med Ethics: first published as 10.1136/jme.24.2.118 on 1 April 1998. Downloaded from

4 Might brain tissue separated from a body can be difficult to define and has been the subject of manifest fear, hopelessness, euphoria or creativity? numerous legal, moral, and ethical debates, this 5 Does the brain-mind unit need a body to have discussion looks the other way. At what level of the qualities of a person? brain activity is the mind functional? If the absence 6 If mental activities occur in laboratory brain ofthis activity defines brain does the presence tissue specimens, how would these activities be of brain activity define life? The brain is a neural detectable? structure which develops very early in , 7 If the mind-brain unit is present in laboratory and continues to develop throughout pregnancy brain tissue specimens should these laboratory and in the first years of life. The brain assumes specimens be used to study mental activities? control over a number of extremely important 8 Can a person give consent for his or her brain functions and becomes responsive to changes in the tissue to be grown or maintained in a laboratory environment very early in the developmental setting if the tissue had or later develops the inde- period. If removed from the head and maintained pendent capacity to respond at some level? would brain tissue have similar functional capaci- 9 Should a human subjects institutional review ties? Could this tissue support mental activities? In board review these activities and how could such a what way are the individual grown in a board determine when a person is being studied culture different from the neurons that comprise rather than a collection of neurons? the brain of an airline pilot struggling to land a damaged plane, a first-grader walking home imag- ining the birthday presents he will receive tomor- 1) Is it possible to grow brain tissue without the row at his party, or of a physician walking into his occurrence of corresponding mind activities? office to tell one of his close friends that the friend There are several useful measures ofbrain activity has a fatal illness? Using the fictitious case of Susan and the absence of these are the most useful crite- referred to by Gillon,' questions 1) and 2) ask when ria for the diagnosis of .9 The criteria does a collection of brain tissue become large for clinical death in use today refer to loss offunc- enough or have sufficiently organized neurophysi- copyright. tion of both the brain and the mind.'" Brain death ological activity to develop mental activities and results in a cessation ofthe brain-mind duality and become a "Susan". the loss ofpersonhood that makes possible the use 3) Should developmental experience be a crite- of all body parts for donation, experimental rion for the brain-mind unit to have the qualities dissection, or simply burial. Relatively little of a person? If a large number of neurons can be discussion has taken place about the maintenance grown in the laboratory setting and then develop http://jme.bmj.com/ or growth of brain tissue in laboratory settings. organized neural activity, could one argue that the Brain tissue grown in a laboratory dish is alive or lack of developmental experience prevents this dead. The "alive" state implies that the cells are at brain tissue from achieving mental activities? some level functional and responsive. The cells Would a lack of developmental experience pre- have and demonstrate some actions clude personhood status so that the tissue would similar to cells that are a part of the human brain always remain just tissue? Must brain tissue be when it is functional. It is obvious that whole attached to a body for developmental experience on September 24, 2021 by guest. Protected brains are not required for mental activity and to occur? psychological development to occur. Herein 4) Might brain tissue separated from a body resides the quiddity of the mind-brain relation- manifest mental experiences offear, hopelessness, ship. Are they, mind and brain, always biologically euphoria or creativity? The constructs used to and functionally linked? There is no evidence that describe or define many mind-brain activities are mental activity exists without brain tissue. But, poorly delineated but at their extremes easily rec- does living brain tissue always equate to mental ognized. The functional limitations of people with activity? From an ethical and philosophical view is profound mental retardation or the prodigious the relationship of brain -o neural activity -* capacity demonstrated by persons with savant mental activity (mind) always present. Or is the skills are easily recognized. People demonstrate a relationship trivial for small amounts of brain tis- wide range of responses to what appear to be vir- sue where the equation could be stated brain -e tually identical injuries. In the locked-in syndrome neural activity (neurochemical and electrical a person is unable to express himself while his organization).mental activity (mind)? brain has considerable functional capacity." This 2) If activity is present in brain tissue does it condition is surely amongst the most tragic of support a mind-brain unit and as a result generate those which afflict human beings. During general emotions, sensations or internally generated mental anaesthetic for surgery brain activity is markedly activity? While the boundary between life and death reduced but, because of the reversibility of this 120 The brain-mind quiddity J Med Ethics: first published as 10.1136/jme.24.2.118 on 1 April 1998. Downloaded from temporary state the persons and their bodies are neurons in a laboratory dish? Would our attitude treated with considerable dignity. However, the change if neurons or brain tissue had the capacity same person, when brain dead, could be used to for such response? For example, what if the demonstrate over a period of weeks to collection of neurons could produce specific EEG first-year medical students, be cremated or changes unique to certain stimuli? How would buried. White and colleagues have removed the life-personhood be defined for this tissue entity? brain from the head of a monkey and kept this 7) If the brain-mind unit is present in-laboratory brain in a container for several days and the mon- brain tissues should these laboratory specimens be key brain had an organized electroencephalo- used to study mental activities? Could one ofthese graphic (EEG) tracing.6 If a similar operation on tissue samples experience fear, anxiety or other a person produced a human brain outside of the psychological constructs used to describe emo- body in a container with functional EEG tracings tions? If so, would use of these samples be an what would be the status ofthe former person and appropriate methodology to study the the present brain tissue? Could a brain in a neurological basis of or the psychological container produce mental activity sufficiently basis of major depression or anxiety? Are there organized to produce psychological states? Even ethical limits to what could be done with or to more important could this brain experience fear, these cell masses? anxiety, pain as neuropsychological events? Would 8) Can a person give consent for his or her brain the status change if an eye or were left attached tissue to be grown or maintained in a laboratory so the brain could perceive and respond to exter- setting if the tissue had or develops the independ- nal stimuli? ent capacity to respond at some level? In some 5) Does the brain-mind unit need a body to have persons with severe removal of one hemi- the qualities of a person? Does attachment to a sphere of the brain above the brain stem is the body confer on the brain-mind unit special treatment ofchoice.'3 Surely, even the most ardent

considerations and separate brain tissue from , philosopher, or ethicist must reflect withcopyright. other organs like a or ? This question wonder on the circumstance of a two-hemisphere is central to the ethical quiddity of the mind-brain brain-mind duality deliberating the destruction of relationship. The perceptual limitations seen in one-half ofitself as a treatment for disease. Is there persons with blindness, deafness, high level spinal a difference in the consent for a procedure from cord injuries or people afflicted with locked-in the verbal half of the brain? How would the non- syndrome, does not alter society's recognition that verbal portion of the brain assent to or dissenthttp://jme.bmj.com/ these people are alive.9 Gillon argues that from a given procedure? Post-operative consent transplanting Susan's brain into George's body by the left hemisphere to experiments carried out, would produce Susan in a different body. A in vitro, on the right hemisphere, appears to be a potential first step in such a theoretical endeavour case of one conscious subject deciding for might well be similar to the procedures used by another, whereas preoperative consent appears to Demikhov." In these animal experiments he be a case of a conscious subject deciding for part grafted the head of one animal onto the upper ofitself. Should these issues be a consideration for torso of another. He published pictures of a dog institutional review boards? Organization of a dis- on September 24, 2021 by guest. Protected with two heads, both lapping milk out of a bowl. If cussion of this issue would need to address several a normally functioning head was transplanted questions: onto the person of a profoundly retarded person what would be the status of both ? Which * What rules of consent would be used if the person would predominate - the higher function- damaged half of a brain after surgery was to be ing head or the intact brain-body unit? Could one kept alive and studied? body be two persons? As we discussed above what * Does one half of a brain-mind have a capacity, is the status of living brain tissue separated from a or the right, to give consent for studies on the body? And lastly an interesting question in the other half after it has been removed from the "Decade of the Brain" is whose health insurance head? Could the diseased half dissent? If so how? would cover the cost of care, Susan's or George's? * What if one proposes to study emotions gener- 6) If "mind" activities occur in a laboratory sam- ated by stimulation of the diseased half after ple of brain tissue how would these activities be removal from the body? Is there a limit to the detectable? It is the presence of activity (response) degree of depression or anxiety that could be in this collection of neurons in the laboratory that studied? Would it be acceptable to produce severe makes them so valued. If the lack of capacity for pain sensations for study? recovery or change defines death what attributes * Do these same arguments apply to a few cells in does the capacity to respond and change confer on a laboratory dish? Burd, Gregory, Kerbeshian 121 J Med Ethics: first published as 10.1136/jme.24.2.118 on 1 April 1998. Downloaded from

* If not, what is a critical mass or at what level of (partial or whole brains)? In what way does the organization does tissue become a brain? removal of a live functioning brain from a person whose body is destroyed in a road accident (where Imagine this discussion with Gillon's theoretical the sole purpose is the maintenance of the brain person, Susan. Susan presents for a hemispherec- for laboratory tests because of the amazing array tomy for some cause, perhaps uncontrollable of responses in this organ) differ from selecting a epilepsy." After extensive using or kidney equally prized for their ability to deep electrode studies, Susan is presented with exhibit biochemical, electrical or structural the interesting option of having her epilepsy sub- changes in response to environmental alterations? stantially improved by a and In the case of liver or kidney, either entire organs also greatly advancing science by consenting for or small cell populations, a liver or kidney is all the excised half of her brain to be used for these cells will be. This is not the case with brain laboratory-based studies. Susan recalls her vivid tissue. If society forbids, or on the other hand of the deep electrode stimulation of the encourages, these activities in the name of science diseased hemisphere to determine what effect a the arguments will encompass both the ethical hemisphectomy would have. She recalls her and scientific domains. Any such discussions will of searing pain with the electrical need to be wide ranging. They will need to include stimulation of one area, the frightening anxiety consideration of the possibility of greater good - provoked by stimulation of a second area, and the for both society and individuals - from continuing profound depression she experienced from stimu- with the study of brain tissue, and also of the lation of a third area. These responses are exactly application of restrictions on these efforts in the the responses the researchers plan to study in the name of individual human dignity. excised brain tissue. What would be an appropri- ate response to the following two questions posed by Susan: Recommendations "Since that part of my brain will be gone these We offer the following criteria for consideration by copyright. experiments will not cause me to feel pain, will ethicists, neuroscientists and human subjects they? "Will I be aware of these experiments?" Is a institutional review boards. These recommenda- person/mind divisible into two fragments that tions are based on three neurophilosophical retain the (same or different) person or mind considerations: qualities? The scenario of one person/mind 1. Human nervous tissues and especially brain http://jme.bmj.com/ fragment consenting to procedures on the other is tissue is unique. Muscle or liver tissues do not a difficult dilemma. Currently the person/mind have the capacity to develop and support mental fragment, comprised of brain only if it in fact activity. exists, would be given the same status by an insti- 2. In , mental activities do not require tutional review board as a skin biopsy, a lobe from whole brains. a lung or a sample. Clearly, the person/mind 3. Animal and computer models may provide fragment in the body retains the original person

adequate models for this research. on September 24, 2021 by guest. Protected and mind qualities. What is the status of the former brain tissue? Does it retain some person/ mind qualities? Does it represent a different TRANSPLANTATION - IN VIVO person and mind? (1) Until the peripheral nervous system can be re-attached whole brain or whole head transplants 9) Should a human subjects institutional review should be prohibited. This is not to imply that we board review these activities and how could such a endorse these procedures if or when the peripheral board determine when a person is being studied nervous system can be re-connected. Our rationale rather than a collection of neurons? Society and for this proposal is that the brain-mind-person medicine have reached a useful and workable construct should function as a part of a complex definition of death. The concept of life requires interactive system. To isolate the brain is to deprive further discussion. The concept of personhood the person of these essential interactions. The loss will also require additional , discussion of two sensory systems in congenitally deaf-blind and definition if society and the neuroscience people has severe developmental consequences community are to develop a general level of leading to severe mental retardation. It is likely that agreement about this issue. How is society to the loss ofall sensory systems will be a neurological come to grips with these issues discussed above? and psychological catastrophe. If transplanted First, should limits be placed on ' efforts early in development these procedures may to develop or maintain living human brain tissue produce mindless brains. Animal and computer 122 The brain-mind quiddity J Med Ethics: first published as 10.1136/jme.24.2.118 on 1 April 1998. Downloaded from models would probably provide appropriate mod- Larry Burd, PhD, MCRH, is Assistant Professor, els for this research for some time. Departments ofNeuroscience and Pediatrics, the Uni- (2) Complete hemisphere transplants should be versity ofNorth Dakota. Jennifer M Gregory, BS, is a prohibited until there is reasonable potential for medical student at the University of North Dakota. functional linkage of both hemispheres and the Jacob Kerbeshian, MD, is Clinical Professor, Depart- transplanted hemisphere to the peripheral nerv- ment of Neuroscience, University of North Dakota. ous system. Both Dr Burd and Dr Kerbeshian are members of the Altru Health Systems Bioethics Committee. BRAIN TISSUE RESEARCH - IN VITRO (3) Research on small cell populations should continue. This research is ongoing and small cell populations appear to have limited potential to support mental activities. References (4) If larger brain tissue masses are utilized for 1 Gillon R. Brain transplantation, and medical research the investigator and human subjects ethics. Journal ofMedical Ethics 1996;22: 131-2. 2 Northoff G. Do brain tissue transplants alter personal identity? institutional review board should discuss the Inadequacies of some "standard" arguments. Journal ofMedical potential for mental activity. Is mental activity Ethics 1996;22: 174-80. 3 Implementation plan for the Decade of the Brain. likely to occur or is mental activity the specific 1990;40: 1483-6. focus of the research? If the conclusion is yes, 4 Lin LF, Doherty DH, Lile JD, Bektesh S, Collins F. GDNF: a would this research be acceptable from a psycho- glial cell line-derived neurolotrophic factor for dopaminergic neurons. Science 1993;260: 1130-2. logical perspective in a person? Ifthe conclusion is 5 McMillian MK, Thai L, Hong JS, Callaghan JP, Pennypacker no, the research should not be approved. KR. Brain injury in a dish: a model for reactive gliosis. Trends in (5) Growing substantial masses of brain tissue in Neuroscience 1994;17:138-42. 6 Verdura J, White RJ, Albin MS. Conceptos actuales en el laboratory settings should continue. However, tratamienta de traumatismos craneocerebrales cerrados. Hom- neuroscientists and institutional review boards enaje en el XXV Anniversario Professional. Dr M. Velasco Sua- rez, 213 (Mexico) 213-222, 1964. copyright. should discuss the potential for mental function- 7 White R J. Experimental transplantation of the brain. In: Rapa- ing and make these decisions with the awareness port FT, Dausset J, eds. Human transplantation. New York: that we do not yet know if this tissue can develop Grune and Stratton, 1968: 692-709. 8 Madrazo I, Lion V, Torres C, Aquilera DC, Varila G, Alvarey F, mental activity. et al. Transplantation of fetal and adrenal (6) Growing or maintaining complete brains medulla to the candate in two patients with Parkinson's disease. New England Journal ofMedicine 1988;318:5 1. without bodies should be prohibited. Develop- 9 Report of the medical consultants on the diagnosis of death to ment of necessary technical advances in these the President's Commission for the Study of Ethical Problemshttp://jme.bmj.com/ areas have grown very rapidly. As in the area of in Medicine and Biomedical and Biobehavioral Research. Guidelines for the delimination of death. Neurology 1982;32: molecular genetics, new developments will quite 395-9. likely far outpace public thought and discussion 10 Bernot JL. Brain death. Archives ofNeurology 1992;49:569-70. eth- 11 Katz RT, Haig AJ, Clark BB, DiPaola RJ. Long-term survival, on the interface between science and societal prognosis and life-care for 29 patients with chronic ics on this issue. locked-in syndrome. Archives ofPhysical Medicine and Rehabilita- tion 1992;73:403-8.

12 Demikhov VP. Experimental transplantation of vital organs. New on September 24, 2021 by guest. Protected Acknowledgement York: Consultants' Bureau, 1962. See also reference 7. We wish to extend our appreciation to the anony- 13 Vining EPG, Freeman JM, Pillas DJ, Vematsu S, Carson BS, Brandt J, et al. Why would you remove half a brain? The mous reviewers whose comments greatly im- outcome of 58 children after hemispherectomy - the Johns Hop- proved this manuscript. kins experience 1968 to 1996. Pediatrics 1997;100: 163-71.