Fight Aging!

At some point in the foreseeable future, it will become possible to grow functional replacement organs and large tissue patches from a patient skin sample in bioreactors. This capability will replace the present insufficient and unreliable donor sources of organs for transplantation. The cost and logistics will be much less onerous, especially if tissue engineering is paired with reversible vitrification, allowing replacement organs to be generated and then kept in storage until needed. Given the present state of tissue engineering, in which an increasing number of functional tissues can be generated in small sizes, and the trajectory of regenerative medicine as a whole, it seems inevitable that these capacities will come to pass. Whether or not they are widely used is an economic question, a race yet to be run between organ engineering for transplantation on the one hand and in situ repair and rejuvenation of existing organs on the other. Some combination of cell therapies and first generation SENS rejuvenation treatments to clear out metabolic waste, senescent cells, and the like could well prove a better choice for patients than undergoing the major surgery of transplantation, even if the transplanted organ is of a higher quality than the repaired aged organ.

There is a way to go yet before organs can be reliably grown from cells in bioreactors, however. Yet on the way to that goal, there are a number of potential shortcuts and transitional technologies that might be (a) be realized more rapidly, (b) allow the creation of useful organs for transplantation, and (c) provide a more reliable and less expensive option than the present system of organ donation. For example, the use of decellularization may provide incremental gains in the number of organs available, and reduce some of the hazards of transplantation. Decellularization involves taking a donor organ, which might include one that wouldn't make the cut for present day transplantation due to cell damage, stripping all of its cells, and then repopulating the organ using a mix of the patient's own cells. This has been accomplished in the laboratory, and perhaps the most interesting implication of this line of research is that the organ need not be human. Pigs have organs of about the right size, for example, and genetic engineering to remove the known problem proteins that might remain in a decellularized porcine organ is a project of feasible scope. Hard, but not impossible. There are research groups working towards this goal today, some already in the commercial stage of development.

Humanized organs in gene-edited animals

Treatment of chronic diseases has resulted in the successful use of cell therapy for the treatment of hematopoietic diseases and cancers as well as device therapies for the treatment of heart disease, diabetes and osteoarthritis. These therapies, while effective, have not been broadly applied to end-stage disease. Currently, curative therapies for advanced end-stage organ failure require transplantation, which is limited by donor organ availability. While millions of patients could benefit from such therapy, the scarcity of organs severely limits the number of transplantations that are performed. This disparity has fueled intense interest focused on alternative organ sourcing and regenerative medicine.

The use of human cells or lineages in a nonhuman animal has been extensively pursued in biomedical research. For example, the incorporation of human hematopoietic stem cells into early, preimmune fetal lamb embryos was demonstrated in the 1990s. These investigators observed significant, long-term, multilineage engraftment of these cells in sheep bone marrow and blood. Additionally, in 2005, functional human neurons in the mouse were developed by injecting human embryonic stem cells into the ventricles of mice. Humanized liver models in mouse have been well established and are currently used for the study of pharmacokinetics and toxicity. In 2001, the repopulation of a mouse liver with human hepatocytes was described. In 2004, human hepatocytes were transplanted into an immunodeficient mouse model to generate chimeric mice with an 80-90% humanized liver. The utility of these chimeric mice in studying human toxicity and dosing and disease is well recognized. More recently, 3D vascularized and functional human livers have been generated by transplanting human liver buds, developed in vitro, into mice. Various studies have demonstrated the capacity for targeted organ chimeras using blastocyst-complementation strategies. For example, a rat pancreas was produced in a mouse by the process of blastocyst complementation. In these studies, blastocysts mutant for Pdx1, the master regulatory gene for pancreatic development, were injected with pluripotent stem cells from wildtype rats. Transfer of the pluripotent stem cells from wildtype rats injected blastocysts and, subsequently, into surrogate mouse dams gave rise to mouse chimeras with functional pancreata composed of rat cells. These studies emphasized the importance of generating blastocysts, deficient for a key developmental regulatory factor, in which the embryo completely lacks the target organ. The blastocyst-complementation strategy has also produced organs such as the kidney and liver in rodents, and recently, the pancreas in pigs. The results of this latter study are significant, because it supports the notion of generating human patient-specific organs in pigs that can be subsequently used for transplantation or advanced therapies.

Groundbreaking scientific advances are bringing the scientific field closer to the reality of developing human organs in nonhuman animals. First, the advances in developmental biology have identified master regulators that are both necessary and sufficient to specify stem cells and direct them to differentiate to distinct lineages. Second, the ability to reprogram human somatic cells to a pluripotent stem cell state, human induced pluripotent stem cells (hiPSCs), has revolutionized the field of regenerative science and medicine. Third, genome-editing technologies, such as clustered regularly interspaced short palindromic repeat, allow for site-specific genome editing. Fourth, the ability to successfully perform somatic cell nuclear-transfer technology (i.e., cloning) in large animals has allowed for the genetic engineering of large animal models. The intersection and combination of these four emerging technologies makes feasible the ability to delete the genes that govern tissue or organ development in a host, thereby establishing a niche for humanized cells. In addition, the use of complementation experiments, where hiPSCs are transferred to a mutant blastocyst, followed by the transfer into a pseudopregnant host, could result in the potential rescue of the host phenotype rescue with a humanized organ. Therefore, it may be possible to engineer personalized organs in large animals and/or engineer unique human disease models in a large animal for preclinical testing of potential therapeutic agents.

Thus farming may well turn out to be one noteworthy component of the organ engineering industry that will arise over the next few decades: harvesting organs from animals, probably genetically engineered lineages specifically created for this purpose. With sufficiently advanced genetic engineering and use of implanted organ seeds or other strategies, the organs being grown in these animals could be completely human. Growing the organ of one species in an individual of another is also something that has been achieved in the laboratory. If you, like most people, happen to be comfortable with the ethics of eating meat, you should probably also be comfortable with farming organs for medical use.

For my part I think that there is a lot to be said for not undertaking the mass generation and killing of entities capable of suffering purely for one's own convenience, but given that I support the necessity of laboratory animals in medical research, my objection is clearly more utilitarian than absolutist. At the present time relinquishing the use of laboratory animals in the medical sciences would be worse than continuing use. In any case, in comparison to farming for food, organ farming and other research community use of animals is a drop in the ocean. Still, to my eyes both farming and laboratory studies of living beings are things that we should use technology to do away with - to cease these activities as soon as possible. This is as much a part of the goals of the Hedonistic Imperative as is eliminating suffering in humans. To end the farming of animals is in fact already possible, and could be accomplished given the will to do so. On the other side of the house, progress in computation and simulation will eventually enable the retirement of mice, flies, worms, and other species that researchers use in their studies. So all in all, it would be pleasant should the future include less farming of animals for organs and more generation of organs in bioreactors, but it is hard to predict how these things will pan out in advance. It all depends on the twists and turns of the economics of clinical application.