Progress in the life sciences is moving at an astonishing rate, and today it has become possible to reproduce part of the human brain in a test tube. The brain is a key organ controlling human activity, and there is a need to think seriously about how far we should allow such research to proceed.
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On November 6, 2008, the media reported that human brain tissue had been successfully created from embryonic stem (ES) cells by a Japanese research group. ES cells are pluripotent cells that can differentiate into various types of cell in the body and hold much promise for regenerative medicine.
The research was conducted at the RIKEN Center for Developmental Biology in Kobe. RIKEN's press release stated that while individual nerve cells had already been made from human ES cells, this was the first time in the world that anyone had succeeded in making an organic structure.
The tissue that was made is a fragment of the cerebral cortex, a part of the brain involved in motor and sensory functions and memory. The tissue formed was only about 2 millimeters in size, but it showed the same electrical activity as brain tissue functioning in the human body.
A photo of the formed brain tissue, showing a beautifully layered structure, decorates the cover of the international science journal in which the research report was published. It is undoubtedly an achievement worthy of such attention.
Should We Make Human Brains?
The cerebral cortex is the part of the brain responsible for functions most closely associated with basic human activity. In conducting research to create tissue that functions in the same way as natural tissue from differentiated cells, should brain tissue be treated just like that of other organs, such as the heart and pancreas?
At the time when regenerative medicine research using human ES cells was about to begin in Japan, I wrote the following: "What and to what degree is it acceptable to regenerate parts of the human body? For example, is it acceptable to create a whole brain from central nerves? If the brain is the seat of human personality, and thus a privileged organ, should this be allowed? The idea that brain death equals human death . . . is a view of life and death based on values that the brain is a special organ worthy of such a privileged position." (Nudeshima 2001, p. 59.)
In the years since I wrote this passage, these questions have not been seriously debated in Japan. With the recent RIKEN announcement we need to think about the following issues:
Firstly, we must consider how special the brain is in human life and as an element of the human body. As special treatment is demanded for genes, which are considered the blueprints of life, and human embryos (fertilized ova), which are considered the beginning of life, how about the brain?
Secondly, we need to address what kind of research should be permitted in keeping with the positioning of the brain and how far we should allow this research to go.
In determining the pros and cons of brain regeneration research, we need to fully consider these two lines of questions.
Did Brain Regeneration Research Pass the Ethics Review?
I would like to point out that the reported research of brain regeneration differs considerably from the research protocol that passed the national review.
When conducting research using human ES cells, a two-layer review must be undertaken by the institution where the research will take place and the national government, namely the Ministry of Education, Culture, Sports, Science and Technology (MEXT). Such reviews examine the scientific and ethical validity of the planned research. Since the results of these reviews are announced publicly, it is possible to know of every human ES cell research conducted in Japan.
The RIKEN group submitted a protocol of this research to the national government in January 2004. The publicly announced summary said, "an investigation will be conducted to develop differentiation-inducing factors for dopamine neurons and other neurons from human ES cells, . . . and for methods to isolate and purify differentiated cells" (MEXT, "List of Research Protocols for the Use of Human ES Cells," No. 11). Dopamine is a substance in the brain that is considered to be useful in the treatment of Parkinson's disease. Dopamine-producing neurons are found in the basal ganglia at the base of the cerebrum deep in the brain. In contrast, the cerebral cortex is the outer part of the brain, which is a completely different part from that of dopamine neurons.
This means that, as far as one can gather from the summary, regenerating cerebral cortex tissue was not included in the reviewed research protocol. In the explanation of the applicants to the MEXT review board, it was said only that the main purpose was to induce differentiation of dopamine neurons. It is doubtful that in later discussions by the review board the regeneration of brain tissue using differentiated neurons was envisioned, and so the pros and cons of such regeneration were never debated at all (Expert Committee 2004). The national review was held only this one time, and the period from application to approval took less than two months. This indicates that the planned research was simple in nature, involving only the differentiation of cells.
The same RIKEN group announced in August 2008 that they had succeeded in creating cells of the hypothalamus, another part of the brain, from human ES cells. The hypothalamus is located deeper in the brain than the basal ganglia, contributing to emotional functions as well as hormonal regulation. The attempt to regenerate the hypothalamus was not in the submitted protocol either. It could perhaps be said, however, that this is included in "differentiation-induction of dopamine neurons and other neurons."
Science is an attempt to clarify unknown phenomena, and an essential part of this is the need to do things that were not initially envisioned as research progresses. However, it is a huge leap both scientifically and ethically from the creation of isolated nerve cells to the creation of tissue of the cerebral cortex, which fulfills a function in the living body. At the point when the research team found this possibility, it should have revised its research protocol and submitted an additional application for review.
Scientists Should Openly Ask the Public
The problem, of course, is not the procedures of ethics review. What is important is that we must think carefully about how far we should allow research to proceed once we learn that part of the human brain can be made in vitro.
With these RIKEN results, it may have been that after they differentiated the nerve cells according to the submitted protocol and attempted various culture methods, the cells naturally organized themselves into brain tissue, and the researchers did not do this intentionally. If that was the case, greater humility should have been exercised in the face of life phenomena that are beyond our comprehension. It is not my intention to stifle the freedom of scientists to carry out bold experiments, but I would like them to adopt an attitude of openly raising issues with the public about whether it is all right to proceed with brain regeneration research.
Ban on Regeneration of Sperm and Ova
In the ethical guidelines of the national government, which sets the range and conditions for permissible research using human ES cells, there are no provisions specifically regarding brain. However, the guidelines do clearly indicate cells that must not be created. They are sperm and ova.
ES cells are created from inner cell clusters extracted from an embryo. Returned to the womb, an embryo can grow into a human being. So it is considered the beginnings of life and must be given utmost respect. Following this logic, cautious handling is required not only in research to create ES cells from embryos but also in research using ES cells created from embryos, and national reviews are compulsory.
It is forbidden to create sperm and ova because they can be used for fertilization to create an embryo and artificially start human life. However, there are growing questions that while the ban on embryos should be accepted, such special regard does not need to be extended to the earlier stage of sperm and ova. As a result, in March 2008 MEXT established an expert committee to examine this issue, and it is said that the committee almost reached a conclusion in favor of lifting the ban on the creation of sperm and ova. At this point, however, the creation of these cells is still not permitted.
Beginnings of Human Consciousness
In contrast, the propriety of creating brain cells and tissue has not been questioned, as mentioned above, and this is why the RIKEN study was possible. Although we may be moving in the direction of lifting the ban, it still should be asked whether it is reasonable to forbid the production of sperm and ova while saying nothing about the brain. Balance seems to be lacking.
A fertilized egg is the beginnings of human life, and if we are going to view it as something that should be respected and not treated lightly as experimental material, then should not we also treat brain tissue that shows electrical activity - which could be called the "beginnings of human consciousness" - using a level of care appropriate to that position?
In both Western countries and Japan, it has been decided that human embryos may be manipulated outside the body only up until 14 days after fertilization. This is because after that time the part that will become the future brain is formed in the embryo. Once the foundation for the brain is formed, the clump of cells is considered to have become an existence close to being human, and manipulation of it is no longer allowed. This reflects the high regard with which the brain is viewed.
Thus, creating or manipulating the "beginnings of consciousness" (such as making cortical tissue and transplanting it to a human) could be regarded as carrying a risk of violating human dignity equal to or above that of extinguishing the beginnings of life (such as destroying an embryo to make ES cells). I think we must carefully examine this issue.
A Proper Status for the Brain
How special is the brain in human life and the human body, and how much care is needed in dealing with it? Should artificial creation and transplantation of brain tissue be allowed? How far should intervention in the human brain be permitted for the purposes of research and medical treatment? These questions have not been adequately explored thus far either in Japan or other countries.
A straightforward example is how the brain is dealt with in French bioethics laws. They cover the widest range of any equivalent law in the world, from genes to cells, organs, and personal information. Although French bioethics laws cover nearly all elements of the human life and body, there are no specific provisions for the brain, which is not distinguished from other body tissues in terms of use in transplantation and research. In the area of ES cell research as well, there are no provisions prohibiting the regeneration of brain tissue.
The French bioethics laws are reviewed every five years in line with developments in medicine and science. Brain science is one of the issues for discussion leading up to the next review, scheduled for 2010. So far, however, the main issues are problems arising from measurements and manipulation of brain functions (for example, the risk of discrimination due to differences in quantified abilities, or whether it is right to enhance memory with the use of drugs). There has been no discussion on regeneration or transplantation of brain tissue, but it will be very interesting to see how things progress from here.
Treating the Brain with Disrespect?
What I would like to say most about RIKEN's brain regeneration research is that, while we hold a nebulous idea of the brain's importance as an organ associated with the essence of being human, little concern is paid to its handling in actual laboratories. As a result, our treatment of the brain seems disrespectful.
One sign of this is the boom in brain science in recent years. Brain science today is mainly concerned with measuring the parts of the brain that are activated when human subjects are given stimulation, and analysis of cognitive and affective functions. As a result, it is widely said that the frontal lobe becomes active when playing games or making calculations. Some claim that brain functions are improved or that this prevents senility in older people (in fact, we know only that blood flow or metabolism around the site becomes more active but not the mechanism behind how specific functions are achieved). The popularity of the game software called Brain Training is a straightforward example of this. Is not the brain viewed as a simple instrument panel or tool that shows our abilities?
The same kind of neglect of the brain is seen even in the field of bioethics. When the Human Genome Project started as a national research program in the United States in 1990, a budget was specifically created to study ethical, legal, and social problems that may arise with genetic research. This approach spread to Europe and Japan and led to the institutionalization of bioethics research. In the brain research project that began in the same year as the human genome, however, no such ethical framework was made.
Later, around 2002, we saw the appearance of a special field called neuroethics to consider ethical issues in brain science. This, however, was a voluntary movement of researchers, not something where the incorporation of ethics research as part of scientific research was officially recognized, as with the Human Genome Project. This has always been a mystery to me, because where human dignity and ethics are involved the brain would seem to be much more important than genes.
Neuroethics has finally started in earnest, but while we see its discussions on whether it is acceptable to use nerve cells or brain tissue transplants not only to treat diseases but also to enhance cognitive functions, we hear nothing about the problem of whether it is acceptable to make brain tissue itself.
In general, the way problems are presented in neuroethics leans toward a focus on the possible misuse of the results of research. Questions are lacking about the problems of the research itself, questions as to how far we should go in using the human brain as an object of research.
Freedom of Scientific Research and 21st Century Society
While the recent findings in the life sciences are exciting, one also has a sense of unease that is difficult to shake. The twenty-first century has been called the century of life science, but this unease is a feeling that people will continue to carry even in this century, or perhaps because of it. Researchers have an obligation to make serious efforts to allay such anxiety in society.
How freely should life science research be conducted, and what should and should not be allowed in this research? These questions need to be asked on an ongoing basis. This is essential as a basis to maintain society's trust in science and also a crucial issue to build basic principles for bioethics policies.
I hope that RIKEN's achievements in brain regeneration research will serve to stimulate renewed thinking about how we regard the brain and discussions to build a foundation for the relationship between science and society.
References
Nudeshima, Jiro. 2001. Sentan iryou no ruru (Rules for Advanced Medicine). Tokyo: Kodansha Ltd.
Expert Committee on Specific Embryonic Body and Human ES Cell Research. 2004. "Minutes of the Eighteenth Meeting." Bioethics and Biosafety Commission, Council for Science and Technology, MEXT (March 5).
