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Human-Pig Chimeras & Liver “Buds”: ethical reflections on two recent biotechnologies

Two recent stem cell studies by Japanese scientists have caught the attention of the media.  They may have implications for human medicine.  The first may allow scientists within a few years to grow human organs inside of living animals for use in organ transplantation.  The second involves the use of stem cells to create complex organ tissue.  Both use a form of stem cell technology referred to as “cellular reprogramming” and the creation of what are known as induced pluripotent stem (iPS) cells [1]about which we have written previously.

In the first study [2], scientists at the University of Tokyo genetically modified a white pig to block pancreas formation.  From that pig they produced an embryo that possessed the same deficiency (i.e., the embryo was not able to produce a pancreas).  They then took embryonic stem cells from another normal pig, a black one, and injected them into the white pig’s embryo and implanted the embryo into the uterus of a third pig.  The piglet with the genetic incapacity to generate its own pancreas was born with the black pig’s pancreas.  The stem cells apparently compensated for the pancreatic deficiency. 

Why is this significant for humans?  The scientists believe that human stem cells—iPS cells—soon will be able to be injected into a similarly modified pig embryo.  The human cells would in theory compensate for the pig’s pancreatic deficiency by generating a pancreas in accordance with their own dynamisms.  Thus the developing piglet would grow with a human pancreas that could be used for transplants into patients.

I asked my friend Maureen Condic, a neurobiologist at the University of Utah, School of Medicine, if she saw any ethical problems with this technology.  She did, explaining that the human iPS cells injected into the pig embryo would not merely localize in the region of the developing pancreas and expend themselves exclusively on pancreatic formation.  In this way, the technology is not comparable to receiving a pig or cow (porcine or bovine) heart valve.  Rather, the human cells contribute randomly and in unknown proportions to the development of the fetal pig, including producing human neurons and gametes. 

The procedure would not create a neat pig-incubator for growing human organs.  It would create a human-pig chimera, a hybrid organism that might have 30% or more human brain cells and make human sperm. (I say “might” because the proportion of human cells incorporated into the pig is uncontrollable.)  This raises a question that seems to me can only be answered with precision by performing unethical research: where do we draw the line between chimeric embryos that are essentially non-human, because the contribution of human material is marginal; and those that possess the moral dignity due to humans? (Think of H.G. Wells’ horror classic, The Island of Dr. Moreau [3])  Doesn’t such research require the willingness to create chimeric organisms that cross the line?

There is also the question of whether it is safe to transplant into a human being an organ that was not only grown in a pig, but that was the pig’s organ for a time, albeit an organ with a human structure.  Could we rule out serious immune problems?  Would we be unethically exposing patients to dangerous pig toxins and pig-specific diseases?  These questions could not be answered without a substantial body of research on non-human subjects demonstrating the safety for human transplantation purposes.

The second study [4], carried out by researchers at Yokohama City University, claims to have successfully engineered for the first time a human internal organ using stem cells.  The researchers began by creating “liver progenitor cells” from human iPS cells.   A progenitor cell is like a stem cell in that it is not yet fully differentiated.  But it is more differentiated than a stem cell, somewhere in between a stem cell and its fully differentiated “target” cell.  Unlike a stem cell, it cannot replicate indefinitely but possesses a limited capacity for cell division. 

The researchers co-cultured the liver progenitor cells with cells that line blood vessels (endothelial cells) as wells as with adhesive cells that join cells together (mesenchymal cells).  They found that the three cell types organized into tiny ball-shaped structures (about 5 mm across) called “liver buds” that functioned like little livers.  When the liver buds were transplanted into mice, they developed vascular links with nearby blood vessels and carried out liver-specific functions.  They also prolonged the survival rate of mice with liver failure.

The researchers hope [5] to apply the technology within a decade to the treatment of humans, especially babies, with liver disease.  Their plan involves creating liver buds from the three types of cells mentioned above (human iPS cells derived from umbilical cord blood, endothelial and mesenchymal cells), and then delivering the buds using IV infusions directly into a diseased liver.  The hope is that the buds would replace the functioning of the damaged liver cells.

Whether the technology can be successfully transferred to humans is still to be seen.  Safety studies will have to be performed before tests can be done on human subjects.  But this type of promising adult stem cell research seems otherwise ethically unproblematic.

It is worth noting that both of these technologies use iPS cells, the celebrated alternatives to embryonic stem cells developed in 2006-2007 by Japanese researcher Shinya Yamanaka, who won the Nobel Prize in Physiology or Medicine in 2013 for the breakthrough.  We have argued at the Culture of Life Foundation that iPS cell research in itself should be supported by defenders of the human embryo as a morally licit [6]alternative to embryo destructive experimentation [7].

We can see, however, especially in the first study above, how the technology can be used in morally problematic ways.  The problems, however, are not intrinsic to iPS cell research itself, but stem rather from the use of iPS cells in ways that violate human dignity. 

Both technologies illustrate how iPS cells are rapidly being utilized for the development of future therapies.  Up till now iPS cell technology has only been used for research purposes.  Many people have set their hopes high for the use of the technology in the fields of regenerative medicine, pathological research and drug development.  Others have argued that the technology will be limited because of the possible deleterious impact of iPS cells on the human body.

Interestingly, on June 26, 2013, the Japanese health ministry announced that it has given a preliminary green light to a team of researchers at Kobe for the world’s first clinical application of iPS cells.  Their study will involve surgical transplants aimed at treating age-related macular degeneration.  This will take place less than ten years after Yamanaka made his historic announcement.

Bioethics
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Where do we draw the line between chimeric embryos that are essentially non-human, because the contribution of human material is marginal; and those that possess the moral dignity due to humans?
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