September 30, 2011

Brain Dead Patients as Research Subjects

N.B.: This is an article written to present what transpired at the recent symposium.  It provides information so that the reader may contemplate the ethical issues at play.  Please see the accompaning commentary for opinions concerning this research.
Brain Dead patients as research subjects in Xenotransplantation
The Future of Medical Research in Toledo, Ohio?
Brian J. Burke, VP CMA-SS
It is common knowledge that there are many, many individuals in need of organ transplants.  The numbers are truly staggering.  The waiting list is up to 112,391 individuals as of 9/30 6:48pm.   What is society to do?  Is there a way in which those individuals who have been declared ‘brain dead’ and yet cannot donate organs could bring about a solution? 
To this end, Michael Rees M.D. Ph.D., a urologist by training and transplant surgeon by practice in Toledo, OH, organized a symposium on September 30, 2011 to discuss a possible solution.  Dr. Rees’ research has focused on an area of transplant medicine known as xenotransplantation.  The idea is that an organ from another species could be transplanted into a human in order to replace the human’s diseased organ.  Now, it is not as simple as simply taking a cow or pig liver and putting it into a human.  The immune systems would not accept the organ as it is, so for the last several years scientists and physicians have been working to create genetically modified pigs.  These pigs would have genes altered that would allow the organs to become compatible with the human body, and in recent years, there has been success in this arena. 
Another, and related area of research, has been developing a way of sustaining liver function outside of the body.  This is an area in which Dr. Rees participated during his Ph.D. at Cambridge.  He worked with a team who were able to successfully sustain extracorporeal (outside of the body) function of a pig liver with it hooked up to a specialized machine.  The machine and the liver could then be used like a kidney dialysis machine, only for the liver function rather than kidney function.
With this machine and a pig liver that has been genetically modified, this idea has come much closer to reality. However, it turns out that the pig liver, even when modified, still will not function.  In this case, it is not that the human immune system attacks the porcine liver, but rather that the pig liver destroys the human red blood cells.  This occurs because of one little molecule on the red blood cells, N-acetylneuraminic acid.  These molecules bind to a receptor on the kuppfer cells (filtering cells) in the pig liver and cause the red blood cells to clump together and be destroyed.  Thus, if you run human blood through a modified pig liver, the blood cells will be destroyed until all are gone.  Now, this can be overcome, and has by Dr. Rees and his lab, by using monoclonal antibodies that bind to the receptor on the kuppfer cells, thus blocking the ability to bind the red blood cells.  This looks very promising, and it is conceivable that in the near future, this system may work.  The next step will be to continue testing the safety and efficacy of this method.
According to Dr. Rees, this is where everything gets very complicated.  Mentioned above was that one little molecule, N-acetylneuraminic acid.  As it turns out, this molecule is fairly unique to humans. Most other animals have a similar, but different sugar.  Even among non-human primates (the usual test subjects for such experiments), this sugar does not exist in the same quantities and distribution.  In practical terms, this means that if non-human blood is run through the modified pig liver, the same effect of having the blood cells destroyed does not occur.  In other words, one cannot truly test the safety of the extracorporeal liver on non-human primates because the problem does not exist in those situations. 
So the crux of the problem is that there is a device, an extracorporeal porcine liver, that could be used to filter human blood, but there is no way to safely test it.  The discussion of this problem and a possible solution was at the heart of the symposium organized by Dr. Rees.
The title of the symposium held at The Toledo Club, in Toledo, Ohio, was “Brain dead patients as research subjects in Xenotransplanation.”  The goal, as stated by Dr. Rees was to bring together individuals in the local community who would have a stake in such a project, and to discuss how this would be received by the community and whether this was legal and ethical to do.
To this end, the first talk of the day was given by Dr. Gretchen Tietjen, a neurologist at the University of Toledo Medical Center.  She spoke on the concept and determination of brain death.  Her main focus was the criteria that has been established by the American Academy of Neurology.  She did not touch upon any of the ethical issues surrounding brain death, but assumed the legality and spoke solely on the medical determination of brain death.  One area she did touch upon were some of the diagnostic pitfalls involved in determining brain death, such as not having the skill to interpret exam findings, applying the criteria to ineligible patients, and not recognizing other syndromes that may mimic brain death.  She made the point that there are no documented cases of recovery of individuals who were determined to be brain dead by the American Academy of Neurology 1995 criteria.  This being said, there are cases such as that of Zack Dunlap, where individuals declared brain dead, have recovered to some degree from their injuries.  Dr. Tiejten did not mention these types of cases in her discussion.  It is also important to clarify just what it means to be ‘brain dead.’  This is a state of existence where medicine has said that all brain function has ceased.  In this case, the other body systems are still functioning (some may require assistance of a ventilator or medications), but the brain no longer is functional nor does it control the rest of the body any longer.  So the idea is that the body is still functioning as it was prior to ‘death’ but that the person is no longer present because the brain has ceased functioning.  In these cases, metabolism still occurs, the immune system still functions, growth will continue in tissues and organs.  It is important to keep these ideas in mind throughout the discussion.
The symposium talks were moderated by Arthur Caplan, a bioethicist at the University of Pennsylvania.  He had a variety of observations, one of the areas he returned to, both after this talk and others, was the issue of trust.  He made the point that organ transplantation, and much of medicine for the matter, hinged upon the trust between patients and their families and the physicians caring for the dying.
The next talk in the morning was given by Susan Martyn, of the University of Toledo College of Law.  She spoke on the legal issues surrounding research on brain dead patients.  The take away message of this talk was that individuals who have been legally declared brain dead fall into a bit of a gap in the law where research is concerned.  Though the laws governing use of corpses and laws governing organ donation do have some role, there is a gap in regards to research.  In the end, they do not fall within the current scope of protections given to human research subjects or under the jurisdiction of Institutional Review Boards.  Ms. Martyn did suggest that an individual IRB could expand its own scope and govern such research, but that it is not required to do so by law.  This leaves many questions about how such research would be conducted and the patients and their families protected from abuse.
The final two talks of the day were given by Dr. Rees.  He spoke of xenotransplantation and the research described above.  These were well presented and created much interest in this kind of research among those attending.   The summary of his proposed project is thus: The team would seek out from the local hospitals individuals declared brain dead whose organs are not suitable for transplant.  These bodies would be transferred to another facility where the experiments would take place.  The experiments would be of three parts.  The first part would be to hook the extracorporeal pig liver up to the body like a dialysis machine and watch for any harm that may occur to the body.  The second part would to see if the antibody that keeps the pig liver from destroying blood cells works and/or harms the body.  The third part would be to actually induce liver disease in the body and to see if the extracorporeal pig liver can compensate.  Each of these experiments would initially take 3-5 bodies and may take 1-2 years each.
And yet, amid the discussions that occurred between the audience and speakers, there were many concerns raised.  The majority of the attendees accepted brain death as fact, but for those who do not, initial qualms are raised in that regard.  But even accepting brain death as a fact, there are still many concerns.  How will the public react to this type of research?  Is the yuk factor so great that it will be a public relations nightmare?  Is the “yuk” factor raised because the public is concerned about respect for the bodies and for the families?  And how would these individuals or families be consented for such research and is that even truly possible?  Others were concerned about the shear cost of such a venture.  Would the money spent on this be better spent on preventative services that would decrease the need for organ transplants?  And in regards to the technical aspects, would it even be possible to sustain the body functions long enough to perform the experiments?  Other individuals saw this in a more positive light and argued that this could be the future of medical research in Toledo.  It could bring great fame and attention to Toledo, and be a source of future growth in medical research for the area.
All of these issues were raised, but the discussion at this time did not move forward.  It was the hope of Dr. Rees that this would be the first of many discussions so that these questions could be addressed.  He spoke of bringing more local leaders to the table, and seeking out those that may raise objections to this project so that they could be heard and their concerns addressed.  The timing of the next meeting was not announced, but based upon Dr. Rees’ interest and investment in this work, it will likely be sooner than later.
This symposium created more questions than it answered, and the very future of the project is yet undecided.  It is important for the reader to consider such a project and know that this could be the future, right or wrong, of medical research.

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