In a remarkable—if likely controversial—feat, scientists announced today that they have created the first successful human-animal hybrids. The project proves that human cells can be introduced into a non-human organism, survive, and even grow inside a host animal, in this case, pigs.
This biomedical advance has long been a dream and a quandary for scientists hoping to address a critical shortage of donor organs.
Every ten minutes , a person is added to the national waiting list for organ transplants. And every day, 22 people on that list die without the organ they need. What if, rather than relying on a generous donor, you could grow a custom organ inside an animal instead? In the past, human-animal chimeras have been beyond reach.
Such experiments are currently ineligible for public funding in the United States so far, the Salk team has relied on private donors for the chimera project.
Public opinion, too, has hampered the creation of organisms that are part human, part animal. But for lead study author Jun Wu of the Salk Institute, we need only look to mythical chimeras—like the human-bird hybrids we know as angels—for a different perspective. There are two ways to make a chimera. When scientists discovered stem cells, the master cells that can produce any kind of body tissue, they seemed to contain infinite scientific promise.
But convincing those cells to grow into the right kinds of tissues and organs is difficult. Cells must survive in Petri dishes. Scientists have to use scaffolds to make sure the organs grow into the right shapes. And often, patients must undergo painful and invasive procedures to harvest the tissues needed to kick off the process.
However, it took Belmonte and more than 40 collaborators four years to figure out how to make a human-animal chimera. To do so, the team piggybacked off prior chimera research conducted on mice and rats. Other scientists had already figured out how to grow the pancreatic tissue of a rat inside a mouse.
On Wednesday, that team announced that mouse pancreases grown inside rats successfully treated diabetes when parts of the healthy organs were transplanted into diseased mice. The Salk-led group took the concept one step further, using the genome editing tool called CRISPR to hack into mouse blastocysts—the precursors of embryos.
There, they deleted genes that mice need to grow certain organs. When they introduced rat stem cells capable of producing those organs, those cells flourished. The mice that resulted managed to live into adulthood. Fertile hybrids create a very complex problem in science, because this breaks a rule from the Biological Species Concept—that two separate species should not be able to breed and have fertile offspring.
Does this mean the parents of these fertile hybrids are not separate species? No, it just means that the Biological Species Concept is not suitable for every species. Thanks to the discovery that some hybrids are fertile, scientists continue to debate what a species is and probably will do so for many years. This is what makes hybridization is so interesting—it challenges some of our basic scientific ideas [ 1 ]. When hybrids mate with either of their parent species, their offspring are known as backcrossed hybrids [ 1 ].
In Figures 2A,B , we see a liger, a hybrid between a lion and tiger that has mated with a tiger. The baby from this mix, the backcrossed hybrid, still has some lion genes. If backcrossing continues for many generations the backcrossed hybrid mates with a tiger, then its offspring does the same the percentage of lion genes will get smaller and smaller, but they are not lost completely. When one species contains some of the genes of another species, it is known as introgression.
This is a powerful evolutionary force, because these new genes may code for new traits or behaviors that could help the parent species [ 5 ].
So far, we have only spoken about hybrids created by humans. Lions and tiger never meet naturally in the wild, but other hybrids do occur naturally. In fact, there are hundreds of hybrids in the natural world.
It is thought that one in four plant species, and one in ten animal species, hybridize [ 6 ]. Hybridization can help parental species by transferring new genes, through introgression, and can even lead to the creation of new species [ 5 ]. For example, South American Heliconius butterflies have gained part of their beautiful wing patterns through hybridization Figure 3 [ 7 ]. Heliconius butterflies use their wing patterns to attract mates, as well as to avoid predators, who interpret the patterns as warning signals.
Ancient hybridization of sunflower species has also generated new species in North America. These hybrid-origin sunflowers can live in more extreme environments, where the soil is poor or toxic. Hybridization combined traits of the two parent species, forming a new gene combination in the hybrid that enabled it to live in this new habitat [ 8 ].
Although many of the natural hybrids we have spoken about are from modern species, there are also examples of ancient hybridizations that happened tens of thousands of years ago. These hybrids can be identified even when the parental species are extinct. This is because some of the parent species genes will still be present in a small percentage in the hybrid. Using this method, an ancient hybrid was found to be an ancestor to many species of clownfish like Nemo from Finding Nemo.
Just like the sunflower, the combination of adaptations in this ancient hybrid allowed the clownfish ancestor to live in a new habitat [ 9 ]. As a result, this ancient hybrid is an ancestor to many modern clownfish species. Sometimes hybrids can be bad for the parental species and for the natural world. If hybrids are very successful, there may be so many hybrids that they compete with their parent species for food and living space, which could lead to the extinction of the parent species.
Losing a species is bad for biodiversity and can affect other species in that habitat. When this species loss occurs naturally, scientists do not try to stop it, because it is a natural process.
Loss of a parent species due to hybrid offspring is only problematic when the hybrid is created by humans and introduced to an area where the parent species were not naturally found.
We must act to prevent the extinction of the parent species in these cases. Some question the need for such experiments using closely related primates — these animals are not likely to be used as model animals in the way that mice and rodents are. Non-human primates are protected by stricter research ethics rules than are rodents, and they worry such work is likely to stoke public opposition. Izpisua Belmonte says that the team does not intend to implant any hybrid embryos into monkeys. Rather, the goal is to better understand how cells of different species communicate with each other in the embryo during its early growth phase.
Attempts at growing human—mouse hybrids are still preliminary and chimaeras need to be more effective and healthier before they can be useful. Scientists suspect that such hybrids might have trouble thriving because the two species are evolutionarily distant, so the cells communicate through different means.
But observing cellular cross-talk in monkey—human embryo chimaeras — which involve two more closely related species — could suggest ways to improve the viability of future human—mouse models, Izpisua Belmonte says. Hybrid zoo: Introducing pig—human embryos and a rat—mouse. In the study, researchers fertilized eggs extracted from cynomolgus monkeys Macaca fascicularis and grew them in culture.
Six days after fertilization, the team injected embryos with human extended pluripotent stem cells, which can grow into a range of cell types inside and outside an embryo.
The embryos each developed unique combinations of human and monkey cells and deteriorated at varying rates: 11 days after fertilization, 91 were alive; this dropped to 12 embryos at day 17 and 3 embryos at day She noted that this team, like others in the past, was not able to control which cells developed into which tissues — a key step to master before such models can be used.
Martinez Arias was not convinced by the results. Combining human cells with closely related primate embryos prompts questions about the status and identity of the resulting hybrids. He says this team was thorough in following existing guidelines. These will address non-human-primate and human chimaeras, says Hyun, who is leading an ISSCR committee discussing chimaeras.
Many countries — including the United States , the United Kingdom and Japan — have at points limited research on chimaeras involving human cells. Japan lifted its ban on experiments with animal embryos containing human cells in and began funding such work that year.
In , the US National Institutes of Health NIH announced a moratorium on federal funding for studies in which human cells would be injected into animal embryos. In , the funding agency proposed lifting the ban but restricting research to hybrids created after gastrulation, when the early nervous system begins to form.
More than four years later, the funding ban is still in place.
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