Every 10 minutes someone gets added to the national transplant waiting list. Hundreds of thousands of patients every day are currently awaiting a life-saving organ donation in the USA alone. Many of them are in various stages of liver, heart, kidney, and other types of organ failure. But every day 22 of them will die waiting for a transplant with only about 6000 transplants performed in the USA every year (Donate Life).
Despite the revolutionary benefits that organ transplants have introduced into the medical field, there are still flaws with its process. The demand for organs severely outweighs the amount available (OPTN). The main source of organs is from deceased donors. But what if people didn’t need to die in order for others to live? What if there was a way that we could grow these organs?
The ability to grow human organs in animal embryos has recently spiked a lot of interest in the research world. The National Institute of Health (NIH) released a statement on August 4th, 2016 that they would be providing funding for experimentation of chimeras, animal-human organisms. They have lifted many of their previous guidelines for Human Stem Cell Research based on the premises that chimeras “hold tremendous potential for disease modeling, drug testing, and perhaps eventual organ transplant”. Because of this, the investigations into the use of human stem cells in animals have grown tremendously in recent years, and even months (National Institute of Health).
Juan Carlos Izipusua Belmonte, a professor at the Gene Expression Laboratory at the Salk Institute for Biological Studies, outlines in his article found in Scientific American in October his labs methods of developing a human organ in a pig. The more descriptive objective for this research is to change the nature of an organ from animal to human before it begins development and allow it to grow to full term. At this time, we can harvest it and use it for transplant into humans exhibiting organ failure.
To begin, they delete the pig’s ability to create a functional organ by manipulating its genome using CRISPR/Cas9 enzymes as “scissors”, which cuts out the gene responsible for the creation of a particular organ. For example, in the case of the pancreas, there is a specific gene called Pdx1 that is entirely responsible for the formation of the pancreas in all animals. Deletion of this gene creates an animal with no pancreas. Allowing the fertilized egg to then grow to a blastocyst, induced pluripotent stem cells (iPSCs) containing the human version of the previous deleted animal gene are introduced to the cell. For the case of the pancreas, this would be an insertion of human stem cells containing the human Pdx1 gene. This blastocyst then needs to be implanted into a surrogate mother, and allowed to develop. Theoretically, this then allows the blastocyst to mature to an adult and form a functioning organ, but of human origin instead of pig (Scientific American).
Where are we at now?
In 2010, Dr. Hiromitsu Nakauchi at the University of Tokyo successfully grew a mouse with a rat pancreas. They also determined that the use of iPSCs as opposed to embryonic stem cell, allows the animals to make new organs that are actually specific for a human individual. This increases the likelihood of success for the transplant as it decreases the chance of rejection. It also reduces the ethical concerns associated with working with and obtaining embryonic stem cells, which remains a highly controversial process because of the nature in which embryonic stem cells are harvested, from the tissues of aborted fetuses (Modern Farmer).
Juan Carlos Izipusua Belmonte also states that researchers in his lab have successfully grown human tissue in the blastocyst upon injection of human stem cells into pig embryos. They are still awaiting results from full maturation of the embryos, and for permission from state and local authorities to continue their work. As of right now, they are only allowed to let the pig-human embryos gestate for 4 weeks, upon which time they must sacrifice the animal. This is an agreement they have come to with the regulatory authorities observing their experiments.
Izipusua Belmonte says his team is currently focusing on growing a pancreas or a kidney, due to the fact that they have already identified the gene that kicks off its development. Other genes are not nearly as simple. The heart for example has multiple genes that are responsible for its growth, making it much more difficult to successfully knock out. This means that this ability to grow organs may not necessarily solve all our problems with organ transplants, but maybe only for particular organs, those whose development can be regulated by one gene (Scientific American).
Izipusua Belmonte discusses in depth this fields limitations and strengths in his Scientific American article. Pertaining to the use of pigs as a surrogate, pig’s organs can grow to whatever size needed to accommodate the person in need of the transplant, thus accommodating for various builds. There is, however, concerns with the gestation period of pigs, which is only 4-months, compared to the 9-month period required for humans. There would therefore be a discrepancy in the differentiation time of human stem cells, which normally require a 9-month period to mature. Scientists would have to adapt the internal clock of these human stem cells.
Another problem involves the use of iPSCs as the source of human stem cells. Although avoiding ethical concerns and being more person specific than embryonic cells, as stated earlier, iPSCs are less naïve. This means that these stem cells have some form of differentiation already and the developing embryos have been shown to reject them as foreign. Jun Wu, a researcher in the Gene Expression Laboratory at the Salk Institute with Izipusua Belmonte, is currently working on a way to treat the iPSCs with growth hormones to “react appropriately to a wider range of embryonic signals”. Izipusua Belmonte says that up to date they have shown promising results that this treatment does in fact increase the likelihood of integrating into the blastocyst. This study is still in its early stages, however, so the complete ramifications are still unknown, although they appear promising.
Furthermore, there are still many more problems with these studies. Pigs and humans are not as evolutionarily related as humans and rats, which have shown successful growth of human organs to date. It is possible that human iPSCs could have adapted to be unable to perceive differences in close relatives, but if pigs are further outside of that realm then integration into the blastocyst might be impossible. In this case, other animal hosts will have to be explored further (Scientific American).
The ethical concerns
It is quite obvious that there are some very extreme ethical concerns with this type of technology. I’m sure you’ve even thought of a few yourself while reading this. Due to its recent emergence into the world of science, we do not truly know the full breadth of the ability of this technology. It is possible that the integration of human iPSCs into the embryo could spread to the other parts of the body, possibly even the brain. What happens when we begin to find human nerves and tissues in the pig brain, allowing the pig to be capable of a higher level of reasoning than the average pig?
This ties into the concerns with the classification living chimeric animals. Would this pig be considered half-human? If not, it’s definitely not just a pig, so what does that mean? Where do we draw the line? Also if this pig contains human tissues, it could possibly be susceptible to developing human diseases, which would be disastrous for the transmission and mutation of infectious diseases (Daily Mail).
Christopher Thomas Scott, PhD, Director of Stanford’s Program on Stem Cells in Society, Senior Research Scholar at the Center for Biomedical Ethics and now a colleague of Nakauchi’s, explains that human functioning goes further than just the cells in the brain. He states that “they are going to act like pigs, they are going to feel like pigs” and even if they were to contain a brain made of human tissue, they would not all of a sudden begin speaking and functioning as a human. It is, however, important to note that this may not be as true for animals more similar to humans, such as chimps and gorillas. It is in these cases that such transfer to human tissue would be particularly scary to consider. It is because of this that these types of experiments are banned by the National Institute of Health to be performed on primates, since the complete ramifications of the introduction of human stem cells remains unknown (Modern Farmer).
The actual process for this being that we just grow the pig with the intent of harvesting its organs and killing it is a topic of controversy in itself. The idea of organ farms is particularly concerning to animal rights activists. Pigs have been shown to share our level of consciousness and suffering (Modern Farmer), so it is argued that using them purely for the growth of human organs, harvesting them and leaving them to die is severely inhumane (Daily Mail).
Another concern involves the mating between chimeric animals. It is unknown how the integration of human stem cells into the animal would affect the reproduction system of these animals. As in the case of the brain, it is possible that some of these stem cells could migrate to the reproductive system instead, creating in extreme cases, a fully functional human reproductive organ. This would be absolutely disastrous as it would theoretically lead to the formation of a fully human sperm and eggs in male and female pigs with this characteristic. If two of these chimeras were to mate, this could even lead to an even more extreme case where there would be the formation of a fully human fetus inside of a farm animal (Scientific American)!
When examining all the concerns, both ethical and scientific, it important to review the question raised by Scott: Why is this research important? (Modern Farmer)
The ability to develop this technology to full term animals with human organs opens up the field of clinical medical science to a whole new world of research. As we’ve been discussing thus far, these organs can be harvested and used in life-saving procedures with the possibility of saving thousands of lives around the world!
But the uses of this technology go further than just organ transplants. We could test drugs on animals with real human organs in them, which would allow us to see more clearly the effects that these drugs would have in the human body. This would avoid the many unexpected complications that often come up in human clinical trials and even years after FDA approval. Imagine the ability to determine these effects without losing human lives, or causing further complications in humans (Daily Mail).
Izipusua Belmonte concludes by claiming that they “are nowhere near ready to take that final step of producing chimeric piglets”. Nakauchi agrees stating he wouldn’t expect such a success, such as an actual organ transplant from pig to human for at least another five years (Scientific American).