Regenerative medicine and the role of chimeras
Jack Schofield describes the chimeras in medicine and their future in saving people’s live
“A genetic chimera, in contrast, is just biological tissue that contains cells and DNA of multiple species.”
The complex terminology and nomenclature used by scientists is often criticised for being difficult to read or understand. Scientists can, however, face the opposite problem, where a simple term provokes suspicion or fear in the public.
Recent work by researchers, creating mouse-rat and (the first) human-pig “chimeras” demonstrates how misleading these terms can be. In everyday parlance, the word “chimera” describes the monstrous, three-headed animals of Greek mythology. A genetic chimera, in contrast, is just biological tissue that contains cells and DNA of multiple species.
These chimeras are not the fire-breathing beasts of legend, but examples of a genetic technique which could save the lives of the many patients currently subjected to protracted, purgatorial waits for suitable organ donors.
“In order to genetically match a patient to their new organ, it must come from the patients themselves. What if the patients’ organs could be regrown or regenerated?”
At the moment, if a patient has a defect in a critical organ, a heart, lung or kidney no longer fit for purpose, they are placed on a waiting list for a replacement. They are then left to wait for the death of an appropriate organ donor, or in some cases an altruistic donation. As donated organs are in short supply, many patients remain on the list to their deaths. For those that are fortunate enough to receive such a donation, there are no guarantees that a transplant will succeed. The immune system recognise these donations as “non-self” and potentially dangerous, and launches a reaction which endangers patient health.
Even if a patient survives long enough to receive an organ, and if their immune system tolerates the donation, they still encounter significant challenges. They usually need to undergo long-term immunosuppressive drug therapy, which can be brutal. Research into these drug regimens has improved the one-year survival rates for transplant recipients. Long-term survival, however, is still not certain, due in part to these immunological problems. Although drug therapy may alleviate the problem of immune rejection, they cannot overcome the fact that these organs are not genetically matched to their recipients. As a result, some patients must live with immunosuppression therapy for the rest of their lives.
Genetic chimeras present a solution to this immunological barrier. The principle behind these chimeras is quite simple. In order to genetically match a patient to their new organ, it must come from the patients themselves. What if the patients’ organs could be regrown or regenerated?
Growing human “spare parts”
“[…]human cells can form chimeras with animals such as pigs. If the process is optimised, it may pave the way for human organ generation in these animals.”
This January, a pair of exciting papers were published which promise to accelerate the science behind chimeric organs. The research featured in these papers may lead to a new type of organ transplant. In the future, doctors may be able to grow replacements of a patient’s organs in other animals, removing the need for a donor and reducing the risk of immune rejection. Human tissues and organs, however, are not flexible enough to regenerate on their own – they must be carefully coaxed into the process.
The first of these papers features research from a collaboration between the University of Tokyo and Stanford Medicine. These teams have worked for a number of years in the field of regenerative medicine, developing a technique called “blastocyst complementation”. This technique is used to generate entirely new organs of one species in the embryonic cells of another. One species is made an “organ factory” for the other.
It works by extracting stem cells (pluripotent stem cells, or PSCs) from one species and injecting them into embryonic blastocysts (an early stage of development) from another species. Pluripotency is just a scientific term to describe the flexibility of these stem cells. They are not fixed to one cell type – they don’t have to be skin cells, muscle cells or neurons and can take on any of these forms, like children at school picking a career. Once they do commit to a particular cell type (or “cell fate”), they are said to have undergone differentiation.
The teams from Tokyo and Stanford, led by Dr Hiromitsu Nakauchi, have been working for several years combining the stem cells of rats and mice. A focus of their research has been the regeneration of organs such as the kidney and pancreas. To achieve this, they have “knocked out” (deleted or inactivated) genes which are needed to grow these organs in a rat or mouse. These mutant animals cannot, therefore, grow a particular organ on their own.
Stem cells from the other species are then injected into the mutants, which allows them to grow the organs. They won’t, however, grow the organ that they would have naturally, as these instructions have been knocked out. Instead, they use DNA of the other species to grow its organ instead. A line of code is deleted and replaced with another version. In a paper released in January’s issue of Nature, however, Nakauchi and his team improved upon their previous work and demonstrated its potential for transplant patients.
They began by growing mice pancreases in rat embryos. To test whether an organ grown in another species could be used for transplant, they took cells from these chimeric pancreases and injected them back into the mice. The immune systems of these mice accepted the cells, and immunosuppressive drugs were needed for only a few days. The chimeric cells used were islets of Langerhans, which produce the hormone insulin. As the mice which accepted the cells were diabetic (an insulin disorder), these new cells helped to treat their disease.
Another paper in January, published in Cell by a collaboration led by Juan Carlos Izpisua Belmonte from the Salk Institute in California, added to the excitement surrounding chimera research. Their work focused on human cells, trying to see if the same technique of blastocyst complementation that is succeeding in rats and mice could be applied to larger mammals such as ourselves. They profiled the “chimeric competency” of a variety of human stem cell, examining their ability to form chimeras with pig or cow blastocysts. Pigs and cows were chosen as they have organs closer in size to human organs than the organs of rats or mice. They tested the ability of a range of human stem cells, from “naïve” to “primed” cells, to form chimeras, and found that “intermediate” stem cells were the best at integrating in the blastocysts.
These intermediate cells are somewhere between committed cell types and the flexible naïve stem cells. Mixing human, cow or pig cells was just the first step, testing whether they could form blastocysts. To create actual embryos, they used only the pig cells and injected human stem cells into over 2,000 blastocysts. The embryos which were produced from these injections were then inserted into surrogate pigs. Embryos were collected after 28 days from these surrogate sows. Although many of them died, a small number of these human-pig embryos survived to this stage. Even limited success here serves as proof-of-principle: human cells can form chimeras with animals such as pigs. If the process is optimised, it may pave the way for human organ generation in these animals.
“The idea of human-pig chimeras would have been laughed at by many of us just a few decades ago. Now, papers such as these are accepted as par for the course.”
These chimeras are not scientific hubris, or researchers playing God – they are a response to the problems plaguing organ transplants. Research into genetic chimeras is really only beginning; the experiments described in these papers are promising, but the process is a long way from being applied to patients. The speed at which our ability to manipulate and tinker with the genetic code, the language of life, is accelerating should astonish us. The idea of human-pig chimeras would have been laughed at by many of us just a few decades ago. Now, papers such as these are accepted as par for the course. This is not normal – this is incredible.