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Deserving the Last Great Gift
If there is part of us that we equate with our “self,” it is surely the brain. What feelings and expectations, then, are stirred if we decide to give this part of ourselves—or the brain of a loved one—to be sliced, labeled, frozen, and shipped to a laboratory somewhere in the world to be used for research? The director of one of the world’s largest brain banks discusses the ethical challenges, implied obligations, and standards of behavior that brain banks must meet to earn and retain the trust of those who give the last great gift—one now indispensable for progress against illnesses ranging from Alzheimer’s disease to schizophrenia.
The study of the human brain after death is a relatively recent but increasingly powerful development in neuroscience. Not surprisingly, this study requires brain tissue from people who in life had neurological and psychiatric disorders. Equally important—although less well known—is the often unmet need for the gifts of healthy individuals whose donated brains become the indispensable “normal controls” that enable scientists to spot and characterize what is abnormal in the afﬂicted brains.
Where do thousands of brain scientists worldwide at universities, research centers, pharmaceutical companies, and biotechnology ﬁrms, seeking basic knowledge of the brain or new treatments for speciﬁc diseases and disorders, obtain the carefully preserved and documented brain tissue that they need? The answer can be seen in the explosive growth in the systematic solicitation, storage, and distribution of brains by what have come to be called brain banks. In the mid-1970s, there were just three brain banks worldwide, but today there are hundreds in the United States alone.
Many things make the collection of postmortem human brain tissue complex, but at the heart of the process are the families who must decide to make this ﬁnal gift and to consent for the brain to be removed from the body of a loved one who may have died only hours earlier—perhaps after months of suffering. In the long run, the contribution that these families alone can offer will be made only if they are convinced that their difﬁcult decision will translate into progress that beneﬁts all and if they are given respect and consideration that persists long after the donation has been made.
This complexity lends urgency to the ethical issues that face brain banking, issues such as the nature of informed consent, how donated brain tissue will be used—and by whom—and who shall beneﬁt from the resulting discoveries.
In the Beginning
Neuroscience is a surprisingly young ﬁeld, having completed the transition into a formal discipline as recently as 40 years ago. In 1970, few reputable neuroscientists studied postmortem human brain tissue. At that time, neuroscience research was principally concerned with the study of the less complex neural systems found in vertebrates such as rats, cats, and monkeys and in invertebrates such as lobsters, sea slugs, and squids. Virtually no systematic studies of the human brain existed. Imaging technology that could study living brains was not yet available, and scientists believed that postmortem brain tissue was ravaged both by the illnesses that occurred prior to death and by the deteriorating changes that occurred after death.
That attitude began to change when, in 1968, investigators in England reported that changes observable in the brains of deceased patients with Alzheimer’s disease not only could be accurately quantiﬁed but also correlated very nicely with the extent of deterioration in memory measured while the patients were alive. Unknown at ﬁrst to most neuroscientists, this study began a quiet revolution as neurochemists and neuropharmacologists became intrigued by the neurobiologic basis for changes in diseases like Alzheimer’s.
By the mid-1970s, there were at least three brain banking operations getting started in Canada, England, and Germany. Not long after, scientiﬁc papers began to appear that showed speciﬁc, quantiﬁed neurochemical differences in the brains of patients with Parkinson’s disease (decreases of dopamine in the substantia nigra), Huntington’s disease (decreases of GABAergic markers in the caudate nucleus), and schizophrenia (increases in dopamine receptor binding in the caudate nucleus). One of the pioneer brain bankers was Edward D. Bird, M.D., who started a tissue repository at Cambridge University in the United Kingdom and, in 1978, moved to McLean Hospital, an afﬁliated teaching institution of the Harvard Medical School, where he set up a facility to collect brains from patients with Huntington’s disease and schizophrenia.
Today this brain bank may well be the largest of its type in the world, providing tissue to investigators not only in the United States but also in South America, Europe, Asia, and Australia. Other brain banks developed to serve speciﬁc academic research organizations. Still others were established as for-proﬁt companies, selling postmortem tissue or its derivatives on the open market. This diverse taxonomy of brain banks, expanding to meet new needs, complicates the ethical questions—and the controversies—facing brain banking today.
Postmortem human brain research grew apace in the 1980s as technological advances made it possible to perform sophisticated studies of molecular and cellular changes associated with various diseases. Criticisms of this type of research lessened as quality standards for processing postmortem brains were deﬁned. A particularly important factor is the postmortem interval, the time between death and the processing of the brain tissue. The longer the interval, the greater the deterioration of tissue. As brain tissue breaks down, biochemical and molecular markers are degraded; measurements are no longer as reliable. The structural integrity of the tissue also breaks down, making it harder to analyze the neurons and their dendrites, axons, and synapses. Research can also be confounded by differences in the age of subjects. We now know that the human brain continues to change throughout the life cycle, so it is essential to have available as controls healthy brains of the same age as the diseased brains being studied.
Cut, Freeze, Store, Ship
Brain donation is complex, and each step must succeed to achieve the desired outcome. The initial step involves the donor’s family, particularly the legal next of kin who represents the donor’s wishes. Before death, the donor can register for brain donation, and the legal next of kin usually—but not always—respects that decision. The legal next of kin may decide to forbid the brain to be removed, for example, if there is reason to believe that the deceased donor had changed his mind about organ donation. As with all organ donations, the legal next of kin must sign an informed consent document that, in this case, gives a person or organization permission to remove and process the brain.
After removal, the brain may be processed in many different ways, depending on the organization receiving it. In this modern era of cell and molecular biology, most brain banks attempt to receive the brain fresh, in which case it is carefully wrapped in a plastic bag that is suspended in an ice-water mixture in a bucket. The bucket containing the brain is placed inside a plastic foam shipping container with a cardboard exterior. Brain banks at a distance from where the donation is made arrange for a courier service to pick up the package. If the package must be ﬂown to another city, the ﬂight schedule is carefully monitored, so that a technician will be ready to process the brain as soon as it arrives.
Removed from its packaging, the brain is weighed and placed on a cutting board. With the use of a special knife, it is bisected so that the left and right hemispheres are separated. One hemisphere is preserved in formaldehyde and used to generate a detailed assessment of the pathology related to neuro-degenerative disorders such as Huntington’s chorea, Parkinson’s disease, or Alzheimer’s dementia, which have hallmark changes observable under a microscope that distinguish them from each other. For psychiatric disorders such as schizophrenia or bipolar disorder, no characteristic pathological changes are observable, even under a microscope; but it is still important to rule out the presence of other degenerative changes that would interfere with the detection of abnormalities unique to a given disorder.
The remaining hemisphere is sliced coronally (from front to back), according to a set of standard anatomic landmarks. Using these landmarks helps to ensure that the resulting slices are as comparable as possible to those from other brains. The slices are placed between two metal plates that are laid in a bed of dry ice; liquid nitrogen is poured over them to induce a very rapid freezing of the tissue, which is crucial for preserving its molecular integrity. Later, the slices are fully labeled and stored in freezers equilibrated to –70 degrees Celsius (–94 degrees Fahrenheit), a temperature suitable for very long storage.
Typically, investigators ask brain banks for tissue by disease diagnosis or by brain region. Neuroscientists proposing research on Huntington disease might request tissue from a region of the brain called the caudate nucleus, which is involved in regulating our motor systems. An investigator intent on studying Alzheimer’s disease might request tissue from the hippocampus, which is pivotal in memory and learning. The brain bank’s staff member withdraws the appropriate slices from storage, taking care to keep the tissue frozen so that molecules do not deteriorate.
The Vital Role of Healthy Brains
As postmortem brain research has burgeoned, availability of healthy brains has become increasingly important. By comparing healthy brain samples with diseased brain samples, scientists can take account of many potentially confusing variables, such as the changes caused not by disease but by age and post mortem interval (PMI). In some ﬁelds, it has become the norm to match the sets of brain samples being studied not only for age and PMI but also for sex, hemisphere, cause of death, and drug exposure. Unfortunately, this state-of-the-art matching is hampered by the dearth of healthy brains, so that in too many cases matching must be limited to only two or three potential confounding variables.
By deﬁnition, the category “normal control” refers to most people, although there are still some technical questions as to what constitutes normal. At a minimum, the “normal” individual must have no history of neurological or psychiatric illness, substance abuse, or alcoholism—information obtainable from interviews with the family. Ironically, normal brains are the most difﬁcult to obtain, because potential donors and their family members do not think about brain disease to anywhere the same extent as families affected by, for example, Parkinson’s disease or Alzheimer’s dementia. The latter families know ﬁrsthand the devastation caused by brain disorders that disrupt neurological functioning; they are acutely aware of the need for the greater understanding that can only come from postmortem studies of the brain. Consequently, they are much more likely to belong to advocacy groups and to have information about the importance of brain donation. In contrast, the acquisition of normal control brains requires staff members at brain banks to expend great effort and resources to reach out to the community to encourage normal control families to think about brain donation as an option at the time a loved one dies.
In May 2003, news outlets worldwide reported a scandal in the United Kingdom. Jeremy Metters, M.D., inspector of anatomy in the United Kingdom, released the Isaacs Report, revealing that over a 30-year period possibly tens of thousands of brains had been removed from deceased individuals without the knowledge or consent of their families. (The report itself was named after Cyril Isaacs, whose brain had been retained for research purposes without his family’s consent.) The procedures and research protocols had ignored the Human Tissue Act, the Coroners’ Rules, and other basic ethical codes in place between 1985 to 1997, when most of the brains were removed. In 1999, the United Kingdom had outlawed the removal of organs without the explicit permission of the donor’s family, but only now is the extent of the earlier violations being realized and publicized. The scandal dramatized the importance of obtaining the consent of the legal next of kin of a deceased donor and doing so in the form of a signed informed consent document.
Remarkably, although informed consent in writing has long been integral to the organ donation process in the United States, consistent standards for informed consent documents were not established until recently. In 2001, the inspector general of the Department of Health and Human Services released a report speciﬁcally addressing informed consent as it applied to tissue donation. The report’s executive summary states that there must be public “trust in the tissue banking community” and a conviction that organizations procuring organs will act as “stewards of the gift.” The report emphasizes that families are asked to give their consent at a time of deep vulnerability, when they may be unwilling or unable to absorb detailed information. And yet, to obtain genuine consent and document a deceased donor’s medical history, the family may have to participate in a time-consuming and invasive interview about their deceased loved one. Although earlier ofﬁcial statements had gone a long way in deﬁning the nature of the donation process, the inspector general’s report was intended to guide—and encourage organizations to reﬁne—the process through which families are approached and how much information they are given about the donation process. Over the past few years, organizations representing the tissue banking industry have begun to follow this process, addressing issues raised by informed consent.
For brain banks, however, the situation is more complex. Typically, brain bank staff members interview families by telephone; these families may have received little written information at the time of the donation. People tend to view the brain as an extension of their loved one, so that sensitivities about the use of brain tissue are much greater than they are for kidneys and other organs. But, regardless of how brain tissue may be processed, and despite that it will bear no resemblance to the original donor, the family should be able to expect that the brain tissue will be handled with the same respect that would have been afforded to their loved one while alive.
Who Owns the Brain?
Once a brain has been donated to a brain bank, also known as a tissue resource center, who owns it? Is the owner the family that donated the brain or the brain bank that received it? To explore this question, we must look at the history of legislation and regulation directed at organ donations in the United States. But bear in mind that donation of brain tissue also has distinctive aspects.
In 1987, the National Conference of Commissioners on Uniform State Laws drafted a document called the Uniform Anatomical Gift Act (UAGA), intended to provide guidelines for the donation of organs and other tissues for transplantation, research, and teaching. In 1988, the UAGA was endorsed by the American Bar Association. The UAGA designates hospitals, colleges, universities, and medical professionals as appropriate recipients of donated organs (“donees”). A donee may also be “any bank, storage facility or speciﬁc person needed by the latter facilities to obtain donated tissue.” In a section dealing with Rights and Duties at Death, the UAGA speciﬁcally addresses the ownership of donated tissue. It recognizes that the “rights of a donee created by an anatomical gift are superior to rights of others.”
The UAGA further stipulates: “If the donee accepts the gift, absolute ownership vests in him.” This wording reﬂects the strict legal viewpoint that giving is considered to be an irrevocable act. This principle is critical when an organ is donated for transplantation, and the person receiving the donated kidney or heart must be recognized unequivocally as its new owner—otherwise, a donor theoretically could demand the return of the kidney, likely resulting in the death of the recipient. The situation is rather hypothetical, of course, but it is easy to understand why the authors of the UAGA vouchsafed airtight protection to donees who require a transplantation for therapeutic reasons.
The language of the UAGA seems to afford brain banks a uniquely important role in processing, storing, and distributing tissue to the neuroscience community. But we can also see why brain donation is different from the donation of other organs or body parts (at least until the distant day when transplanting brains may become feasible). Brain tissue is donated for research. The donor is deceased and unable ever to demand the return of the donated brain, but not so the donor’s closest relatives, who could change their mind as to whether they wanted the donor’s brain tissue distributed to laboratories around the country. It can and does happen (albeit rarely) that donor families change their decision and demand that their loved one’s brain be returned so that it can be joined with the other remains of the deceased’s body. According to UAGA guidelines, however, a brain bank would be entirely within its rights to refuse to return the donated brain.
Do organizations that distribute tissue so investigators can advance the frontiers of medical science engage in an ethically different transaction than do organizations that distribute donated organs for therapeutic purposes? If a donor family were to demand that an organ donated for research be returned, no irreparable harm would befall the tissue bank. Given this distinction between organs donated for therapeutic reasons and organs donated for research, can we assume that the same principles about the question of ownership apply in both cases—and that it is appropriate for the brain bank to claim absolute ownership of the tissue?
In approaching this question, it may be illuminating to distinguish between two different types of brain banks in the United States. There are brain banks funded by the National Institutes of Health to serve as national resources, and other brain banks that are funded privately. Both types of brain banks provide research scientists with postmortem brain tissue. In the ﬁrst case, however, the investigators who receive tissue could be located at many different research institutions around the nation. My own institution is an example of this type of brain bank. The Harvard Brain Tissue Resource Center at McLean Hospital in Belmont, Massachusetts, funded by the National Institutes of Mental Health and the National Institute of Neurological Diseases and Stroke, provides postmortem brain tissue to some 100 investigators in laboratories around America. To qualify to receive tissue, a scientist must submit an application that demonstrates federal funding, that the proposed project in which the tissue will be used is at the cutting edge of research, that the laboratory has the necessary resources to conduct this research, and that the principal investigator has been productive in his research. No collaborative relationship exists between the Harvard Brain Tissue Resource Center and the investigator, in contrast to the situation in which a privately run brain bank supplies tissue to investigators engaged in collaborative research with the group maintaining the brain bank, either at the same institution or elsewhere.
Should ownership of the donated postmortem brain tissue vary according to which type of bank one is considering? For brain banks funded by the federal government, the donated tissue or organs are deemed to be in the public domain. They do not belong to any individual or organization; they are dedicated to serving the common good by advancing the research efforts of the scientiﬁc community. Thus, like organs for transplantation, tissues donated to federally funded brain banks can also be thought of as a gift, but one made by the donor to the neuroscience community rather than to any individual scientist or team of scientists. The brain bank receiving and distributing such tissue provides oversight without actually owning the tissue. Returning to the language of the report from the Ofﬁce of the Inspector General for the Department of Health and Human Services, “the tissue banking community…[should] act as stewards of the gift.”
In practice, the situation of privately run brain banks is quite similar to that of the national resource banks in that the tissue is being used for clinical neuroscience applications. Because their mission is to study diseases of the brain, the small collaborative groups that develop private brain banks likewise contribute to the betterment of humanity. When we turn to yet a third type of brain bank, the for-proﬁt medical supply ﬁrm, and consider another category of tissue users, for-proﬁt ﬁrms, additional questions—and one of the most active controversies facing U.S. brain banking today—arise.
The Brain as a Commodity
Should donated human tissue be treated as a commodity? The UAGA noted: “Processed tissue often is marketed and sold like any other medical product. For some people, these practices call into question the nonproﬁt basis of the tissue banking community.”
More than a decade later, the report of the inspector general of the Department of Health and Human Services observed that “treating tissue as a commodity may raise some underlying tensions with families’ assumptions. For example, the family may not be aware of the fact that the tissue is being viewed as a commodity…[to be] marketed and sold as a medical supply, rather than as a donation.” This concern could be met, at least in theory, by using an informed consent document that stipulates that the tissue might be sold for a proﬁt to third parties. Unfortunately, the UAGA did not specify in its standards for informed consent that information of this type should be included in the documents that are used by brain banks.
Can the concerns raised by treating brain tissue as a commodity be adequately addressed by informed consent? Once again, we must understand the varying aspects of the missions of brain tissue resource centers and their relationship to the world of brain research.
The tissue provided by brain banks to pharmaceutical and biotechnology companies —that is, for-proﬁt ﬁrms—is most often used in basic neuroscience research programs that are virtually indistinguishable from those of academic centers. Typically, the goal of research by pharmaceutical and biotechnology companies is the discovery of novel therapies. Academic laboratories could theoretically conduct similar research, leading to the same advances in therapy, but often they lack the resources available to commercial enterprises. So, in fact, supplying tissue to for-proﬁt companies may hasten the discovery of new treatments and save lives.
The goals of these pharmaceutical and biotechnology companies, however, may differ from those of biosupply companies that sell brain tissue or its derivatives to public or private neuroscience laboratories. The biochemical components extracted from donated brain tissue are treated as commodities to be sold on the open market. This is not to say, of course, that both types of companies—those conducting basic science research and those providing resources for this research—are not making positive contributions.
One common concern is the fear of many brain researchers that for-proﬁt companies may be motivated to hoard their scientific data, which, it is widely agreed, is likely to slow the progress of neuroscience research. In recent years, however, there has been a growing trend for scientists at academic institutions to ﬁle patent applications for their discoveries and even to form commercial entities. Clearly, the distinction between the academic and the entrepreneurial world is becoming blurred; investigators at both academic and for-proﬁt companies might hoard their data. One solution would be to require that investigators agree to make their scientiﬁc ﬁndings public in a timely fashion, by publication in refereed journals, for example, or presentations at national and international meetings. All investigators who received tissue from any brain bank would face sanctions for violating their agreement. This sanction would apply to academic as well as corporate scientists, nonproﬁt as well as proprietary enterprises that obtained tissue by entering into an agreement with a brain bank.
A second concern is whether a brain tissue bank, its staff, or both are entitled to a share in the proﬁts emanating from discoveries made by using the tissues from that bank. Federally funded brain banks that serve as national resources have tissue collections that are in the public domain, precluding any proprietary interest in discoveries. But for private tissue banks or other private collections of tissue, the concern remains. One way to address this concern would be for the brain bank to negotiate on a case-by-case basis with the for-proﬁt entity receiving tissue.
A “Duty to Warn”?
It is now well-established among bio-resource companies and ﬁrms doing genomics research (major users of tissue) that informed consent is critical to their proper operation. The informed consent documents used today by U.S. tissue banks are usually relatively simple, however; whereas genomics companies face some exceedingly complex issues raised by their work.
In the United States, the legal next of kin must give consent for brain donation, and this consent typically implies that what is called “tribal consent”—the consent of the family at large—has been given. But when genotyping is performed on a dead relative, something may be learned that is of potentially profound concern to other members of the family, such as information that the relative is the carrier of the gene for an often-fatal disease. Family members may or may not want to share this knowledge of their genetic destiny. Should the consent of the entire family, then, be required for genomics research, so that each member of the family speciﬁes that genotyping of Uncle Harry is okay?
Regardless of what the laws in a given state might dictate, some genomics ﬁrms consider it common sense to ask the family for such tribal permission. The problem could be skirted, of course, by making all donors in a genomics study anonymous. But then is there a duty to warn if a genetic association is made to a particular neurological or psychiatric disorder that could potentially alter the lives of relatives? Some might want to know, but others might not. To avoid this situation, it may be necessary to ask each member of the donor family if he or she wishes to be informed of genotyping results. Because these wishes could change over time, another question is how far into the future should such follow-up information be provided to the family? For example, a genomics database could potentially continue to grow over a period of 10 years or more, during which time new associations between genes and diseases may be established. How long should a duty to inform remain in effect?
Deserving the Gift
As scientists worldwide labor to unravel the mysteries of neurological and psychiatric disorders that afﬂict millions of us, the availability of high-quality, well-deﬁned brain tissue has become essential to the battle. Of the many complex steps in acquiring, processing, storing, and distributing brain tissue, the most critical step remains the ﬁrst: the decision to make this last gift to humanity—and to do so based on full and reliable knowledge, by donor and family alike, of how it will be used. Amid the ethical concerns arising at this stage and later, our guiding light must be consistent respect for both donor and family. This respect includes meeting the reasonable expectation that the body of a loved one will be treated in a sensitive manner, not only in gaining informed consent but also long after the act of donation. Families who make the difﬁcult decision to donate their loved one’s brain for neuroscience research expect to enhance other lives, to bring something new and positive from a death and loss. Even enterprises that deal in brain tissue as a commodity can meet this expectation by ensuring brain tissue enhances disease-oriented research.
At present, ethical questions raised in relation to brain donation tend to be derived from our experience with donation of organs for transplantation. This experience does not precisely ﬁt all circumstances arising in relation to brain donation, not least because of cultural views about the nature of the person and the soul, which for many people are intricately linked with the brain. Science has not typically acknowledged the existence of these issues, but brain banks that collect human brain tissue, and scientists who study it, must understand and respect their power.
Despite all these complex and difﬁcult questions, it is critical for brain banks to continue to provide scientists with adequate amounts of tissue so that progress in understanding the causes and cures of devastating diseases of the brain is not delayed. When dealing with postmortem human brains, we must return again and again to the most basic question: How can we use this precious national resource to provide the most beneﬁt to the most people? It is, likewise, essential that we ask how this research can be done while still respecting the rights and human dignity of the donors and their families who give this last great gift.