Chimeric Organogenesis at a Crossroads
Joe Cornicelli

Chimeric Organogenesis at a Crossroads

Using mouse cells to grow rat organs opens a window to cures for diseases like diabetes. But is the technology outpacing the ethics?

A potential breakthrough for the treatment of type 1 diabetes may be on the horizon. A recent report in Nature by a team of researchers from Stanford University and the University of Tokyo documents the ability to grow, harvest and transplant functional mouse pancreatic islets that were grown in a rat! 

The team accomplished this feat by transplanting mouse inducible pluripotent stem cells (iPSCs) into a rat embryo that had been modified in such a way as to suppress the development of its own pancreases. The process is known as embryo complementation. The rat sized pancreata were harvested from the rats and the islets that were isolated were transferred into mice rendered diabetic using a pancreatic beta cell toxin. Those islets effectively reversed the diabetes without lifelong immunosuppression. 

This proof of concept study effectively opens the door for growing human organs in animals, providing patients with Type 1 diabetes a potential cure. It has effectively demonstrated that organs of considerable size can be generated across species, and that the effector cells from those organs are functional. The most intriguing aspect of the study involved the lack of long term immunosuppression. Yamaguchi and co-workers administered immunosuppressive therapy for a few days following the transplant, but then discontinued it because the cells transplanted were autologous. 

Good news for diabetics 

This exciting discovery is surely good news not only for the estimated 3.7 million Type 1 diabetics worldwide but also for all of the other patients awaiting an organ donation.  Suitable tissue matched donors are in short supply, so in theory, organs could be cultivated on demand for a variety of conditions. For example, it is possible to genetically modify a pig to develop without a heart and then complement that mutation with human iPSCs that would generate a functional human heart. 

All of this is theory at the moment, but some of the significant technological hurdles have been overcome. Nonetheless, the promise of “farmed” human organs is not on the immediate horizon and a number of questions and issues remain. How long will the autologous grafts last? Currently, a transplanted pancreas will be functional for about 5 years in only 57% of patients. Lung transplant have a 5 year lifespan in only 52% of recipients, while liver and heart transplants will survive for 5 years in >70% of patients, according to the Scientific Registry of Transplant Recipients

Another issue relates to what other “baggage” the chimeric derived transplants carry.  Are there any unexpected consequences?  There are certainly differences between species with respect to embryonic development, rate of growth, etc. Ethical issues are certainly going to be center stage in creating animals that contain human cells or tissues.  Is it possible that human germ or brain cells would be recapitulated in a pig? How do we control differentiation? These may be solvable issues, but need to be considered very seriously.  (This relatively recent publication is an interesting perspective on the topic.)

As a researcher who has spent years studying metabolic diseases, I think that we are on the edge of some truly remarkable innovations in treating diseases that were, heretofore, untreatable. The development CRISPR/Cas9 gene editing has already been hailed as a rapid, reliable method for making precise, targeted changes to the genome of cells and animals. I can only begin to imagine how powerful this technique will prove when coupled with embryonic complementation for the treatment of devastating disorders.

I wonder, however, if our technology is outpacing our ability to deal with the ethical issues that are certain to arise.  At what point do we make the jump from treating diseases to practicing eugenics? To be clear, I am not an alarmist and I am not advocating abandoning the judicious application of technology to ameliorating human disease and suffering. I do feel, however, that there is more to consider than the hurdles required to enable this very powerful technology. To paraphrase the comic book great Stan Lee from his Spider Man series, with great power comes great responsibility, and we must not take that responsibility lightly.