by Garrett Dunlap
figures by Shannon McArdel

Every ten minutes, another person joins the list of hundreds of thousands waiting for organ transplants. The wait is sometimes years long, despite many of the candidates being in critical condition. But what if the need for transplant waiting lists could be eliminated? Recent advances in a decades-old technology known as chimerism give reason to believe that this may be possible, curing diseases and improving well-being along the way.

Chimeras: mythological beasts or useful research tools?

In Ancient Greece, a Chimera was a mythological beast consisting of parts from different animals, such as the head of a lion and the body of a goat. But don’t expect to see these fire-breathing monsters coming out of laboratories! In the medical world, a chimera refers to any living thing that is composed of cells from two or more organisms. Because of this, you may in fact already be or know a chimera! For instance, anyone who has received a bone marrow transplant from another person qualifies. After a patient receives one, their blood, which is produced by the transplanted marrow, carries DNA that is different from the DNA contained in the rest of their body’s cells.

But transplanting human tissue is just the tip of the iceberg. Other medical procedures produce chimeras that combine species! For instance, heart valves from pigs are already used in some surgeries to replace faulty valves in human hearts. The pig is a natural choice for human transplantation, as many organs are quite similar in size and structure between human and pig. Unfortunately, the body may reject the pig valve, as the immune system sometimes sees the pig cells as “foreign” and mounts an attack. And so, researchers were faced with the task of developing replacement organs that the human body won’t reject.

Enter the current state of chimera research.

Growing new organs

Scientists have been studying chimeras formed from different animals for over 30 years. The first recorded success was in 1984, when scientists engineered a “geep,” an organism with cells from both a goat and a sheep embryo. Since then, scientists have attempted to generate chimeras again and again for a growing list of scientific and medical applications. Recent advancements in gene editing technology such as CRISPR have made it easier than ever to study chimeras and their possible benefits for human health.

While chimeras seem incredibly exciting, there are some caveats. For instance, the mythological Chimera of ancient Greece is unlikely to ever be physically possible: there is a limit to how different two animals can be and still be chimerically compatible with one another. While we have successfully made a rat-mouse chimera, such is not the case for a rodent-pig chimera. This shows that there seem to be limitations to the distance two organisms can be in respect to evolution. However, as you may have already guessed, human stem cells can be fused with pig embryos to form human-pig chimeras (Figure 1).

The scientists did not attempt to create these chimeras in order to make a species of half men, half pigs, though. The idea is to create an organism in which only one, or possibly a few, of the organs are of cells from the second species. It may then be possible, for example, to grow a “human” heart inside a pig, and then transplant it when a patient with a heart defect or disease requires a new, fully functioning heart.

Figure 1. Chimeras have been successfully made between multiple species, but not all pairs are able to form chimeras. For example, while cells from a mouse and rat could form a chimera, cells from a pig and rat could not. The successful combination of cells from a pig and human suggests that one-day growing “human” organs in pigs for transplantation may be possible.
Figure 1: Chimeras have been successfully made between multiple species, but not all pairs are able to form chimeras. For example, while cells from a mouse and rat could form a chimera, cells from a pig and rat could not. The successful combination of cells from a pig and human suggests that one-day growing “human” organs in pigs for transplantation may be possible.

The future of chimera-based treatment

One particularly exciting potential application of chimeras is the treatment of type 1 diabetes. Type 1 diabetes is a disease caused by a lack or low levels of insulin, which works to keep blood sugar at healthy levels. The disease’s symptoms, which occur suddenly and usually at a young age, are rooted in malfunction of cells in the pancreas called beta cells. Because these beta cells reside in particular areas of the pancreas, it is possible that healthy ones can be transplanted to replace the faulty ones. In effect, a patient may no longer need to routinely take pills or injections to maintain proper levels of insulin. Pancreas transplants are already in use to combat type 1 diabetes. With waiting list times averaging over two years, though, the supply simply cannot keep up with the demand.

Generation of chimeras to produce fully functional pancreases is a potential method to solve this problem. In fact, this idea is currently being tested at the University of Tokyo, where a group of researchers first formed rat-mouse chimeras. Unlike the previously mentioned rat-mouse chimeras that had a random distribution of either rat or mouse cells, these chimeras were all rat except for one organ- the pancreas. The pancreas contained nearly all cells from a mouse, yet still functioned completely fine in the rat. The grand experiment came when the researchers attempted to transplant beta cells from the chimera’s pancreas into diabetic mice (Figure 2). Amazingly, these cells become a functioning part of the diabetic mouse’s pancreas, producing insulin as necessary. As a result, the researchers witnessed that these mice were able to maintain healthy blood sugar levels for over a year!

Figure 2. A chimera with the pancreas of a mouse can be made by combining cells from a mouse and a pancreas-less rat. Then, the pancreas transplanted into a diabetic mouse, where it can produce insulin. As a result, the insulin works to regulate the mouse’s blood sugar, essentially curing it from the symptoms of diabetes.
Figure 2: A chimera with the pancreas of a mouse can be made by combining cells from a mouse and a pancreas-less rat. Then, the pancreas transplanted into a diabetic mouse, where it can produce insulin. As a result, the insulin works to regulate the mouse’s blood sugar, essentially curing it from the symptoms of diabetes.

While chimeras composed of cells from rats and mice may be far from representative of humans, this shows that transplantation of chimera-grown tissues may be the future of treatment for many diseases. This is not without much controversy, though. Only in late 2016 did the National Institutes of Health begin to consider allowing federal money to go toward research on human chimeras. Currently, all studies of human chimeras must be funded either in other countries or using money from private organizations. Even then, restrictions are in place regarding how long a chimera involving human cells can be left to grow. While it will no doubt remain a controversial topic, further research on chimeras may have the ability to one day eliminate the need for transplant wait lists and permanently treat diseases like type 1 diabetes.

Garrett Dunlap is a student in the Biological and Biomedical Sciences Ph.D. program at Harvard University.

For more information:

For more press coverage: First Human-Pig Chimera is a Step Toward Custom OrgansWired

For discussion of ethical considerations: The Chimera Quandary: Is It Ethical to Create Hybrid Embryos?NPR

To learn more about becoming an organ donor: https://www.donatelife.net/

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