Stem cells are recognized for their therapeutic promise in regenerative medicine, and they’re also being used to save endangered species!

Four hours north of Nairobi, closely safeguarded by armed security, the last remaining northern white rhinoceros are waiting for extinction. Only three animals are left, all three of them living in a 700-acre enclosure within the Ol Pejeta Conservancy Park: there is Sadu, a 43 year-old male, the 27-year-old female Najin and her 16-year-old daughter Fatu. Once roaming great parts of Eastern and Central Africa, heavy poaching diminished their number to just a handful of individuals.

The last successful birth of a northern white rhinoceros was in 2000, with all following reproduction efforts in captivity staying unsuccessful. Natural reproduction is sadly out of reach for the last three individuals, with Sadu having a low sperm count, a difficult leg injury of Najin and a uterine disorder in Fatu that prevents her from becoming pregnant.

The sad truth is that many more species will share this dark prospect with the three rhinos. With largely human-made threats ranging from excessive poaching, loss of habitat, climate change and disease, many species are simply not capable of adapting fast enough to endure the ever increasing environmental pressure they are facing. The IUCN Red List of Threatened Species is providing detailed information on the conservation status of endangered species for the past 50 years (video).

White rhinos

White rhinos

Currently it is listing 11,316 vulnerable, 7781 endangered and 5210 critically endangered species, with prominent examples such as the Eastern Gorilla, the cheetah and as one of the latest additions, the giraffe. Similar to the northern white rhinos’ situation, even the most ambitious conservation efforts will come too late for many of them. Conventional conservation strategies, including breeding programs in the wild or in captivity often remain ineffective (especially in captivity) and facilitated methods such as In Vitro Fertilization (IVF) have not been achieved or even tried in most species.

An additional lack of knowledge about the reproductive cycle of most animals makes any breeding efforts a difficult undertaking. And even if breeding efforts were successful, the low diversity in gene pools of bred populations, together with the shrinkage of natural habitats would make the successful establishment of a self-sustaining population extremely difficult.

Amidst this dark prospect, recent milestones in stem cell and reproductive technologies spark new hope among scientists. In November last year, a group of scientists under Katsuhiko Hayashi at Kyushu University in Japan has achieved one of the holy grails in reproductive biology: engineering artificial egg cells from reprogrammed mouse skin cells, entirely in a dis.

Eastern Gorilla

Eastern Gorilla

The foundation for this success originates in earlier work that Hayashi did as student, where he succeeded in converting reprogrammed stem cells into primordial germ cells (PGCs), the precursor cells for both sperm and egg cells. When injected into ovaries or testis of living mice these artificially derived cells gave rise to fertile sperm and egg cells.

Now leading his own lab, Hayashi proved that the last maturation step in a living mammal is in fact not necessary but can be completely achieved in vitro. The derived egg cells were successfully used to give birth to pups which themselves were healthy and fertile. With a similar strategy Chinese researchers recently announced the generation of rudimentary sperm cells in a dish.

With the prospect of reconstituting the entire male and female germ line cycle in a dish, scientists hope to translate this success story to other fields of public interest. While some dream of the eradication of human infertility and the possibility of offspring for same sex couples, it also offers a completely new avenue for species conservation and with that the rescue of the northern white rhino.

In case you were wondering, this is how a giraffe eats.

In case you were wondering, this is how a giraffe eats.

Zoo Dvůr Králové in the Czech Republic – the official owner of the last three northern white rhinoceroses – has now assembled a consortium of mostly European research institutions to make the impossible possible. Members include wildlife and reproduction biology experts from the Leibniz Institute for Zoo and Wildlife Research in Berlin (IZW), stem cell experts from the Max Delbrück Center for Molecular Medicine in Berlin (MDC), the Helmholtz Institute of Stem Cell Research in Munich (ISF), Dr. Hayashi’s lab in Japan, as well as Avantea, an Italian biotech company specialized in Assisted Reproduction services.

Under the title, “Conservation by Cellular Technologies,” the consortium members released an ambitious road map plan early last year, where they sketched out a dual strategy, involving both the collection of natural gametes and – inspired by Hayashi’s success in mice – the generation of artificial ones.

For the collection of natural gametes first trials have been pursued in the closest relative of the northern white rhino, the southern white rhino. By now, oocytes from several females have been successfully retrieved by Dr. Thomas Hildebrandt, head of the Department of Reproduction Management at the IZW. The collected eggs were then shipped to Avantea, an Italian company with renowned expertise in cloning and assisted reproduction of large animals such as horses, cattle and pigs.

Cheetah cub

Cheetah cub

Here the collected eggs were fertilized and successfully developed into early embryos ready for transfer into potential surrogate animals. First results were presented early this March at a two-day meeting of the European Northern White Rhino Working Group at Zoo Dvůr Králové. Encouraged by the first results, members aim to harvest gametes from the two remaining female northern white rhinos as early as this year.

To complement this first strategy, stem cell experts from the MDC Berlin and the Helmholtz Institute in Munich are working closely together with Dr. Hayashi to attempt the production of artificial gametes. For this the scientists rely on frozen tissue material which has formerly been collected from eleven deceased northern white rhinos and is now stored at zoological biobanks, primarily at the San Diego Zoo and the IZW.

Similar to in mice and humans, it was shown that these adult tissue cells can be converted into induced pluripotent stem cells (iPSCs), thereby providing a potentially indefinite source of artificial rhinoceros gametes. Currently, the scientists work on a protocol to differentiate the iPSC lines into primordial germ cells, which may then be matured into egg and sperm cells.

With the consortium road map underway, how realistic is the rescue of the northern white rhino? According to Dr. Hildebrand from the IZW, the first delivery of a northern white rhino may be possible within the next decade, assuming the outlined approach proves fruitful. This groundbreaking work would not only be the last chance to save the (sub)species of northern white rhinos but would also shift paradigms as to what is currently considered possible in today’s species conservation.

mepicChristina studied Cell Biology and Molecular Medicine with special focus on Stem Cell Research and (Epi)genomics. During her PhD she worked at the Harvard Stem Cell Institute und Broad Institute in Cambridge, USA. Currently she is working as a postdoc at the Max Planck Institute for Molecular Genetics in Berlin. 

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