Prometheus unbound

PROMETHEUS, a Titan bound to a rock by Zeus, endured the daily torture of an eagle feasting on his liver, only to have the organ regrow each night. Compared with this spectacle, a video on the website of Nature this week seems decidedly dull. It shows a collection of pink dots consolidating into a darker central glob.

But something titanic is indeed happening. The pink dots are stem cells, and the video shows the development of a liver bud, something which can go on to look and act like a liver. Takanori Takebe and Hideki Taniguchi of Yokohama City University, in Japan, who made the video, have created working human-liver tissue.

Researchers have long dreamed that stem cells might be used to repair or replace damaged tissue, an aspiration known as regenerative medicine. Embryonic stem cells, in particular, are “pluripotent”, meaning they are able to become any other type of cell. And it is now possible to induce pluripotency in cells that have not come from embryos, thus circumventing the ethical minefield previously associated with obtaining them.

Last year Shinya Yamanaka of Kyoto University won a Nobel prize for the invention of induced pluripotency. He had shown how four signal proteins can reprogram adult cells into a pluripotent state. Beside dealing with the ethical problems of embryonic cells, Dr Yamanaka’s induced pluripotent stem (iPS) cells allow—at least in theory—a treatment to be created from a patient’s own body. This would have his own genetic make up and would thus not attract the attention of his immune system. Realising such treatments has been fiendishly difficult. But Dr Takebe’s paper in Nature is one of several signs that the Promethean dream is slowly coming to life.

Budding hope

Clinical trials of pluripotent cells are already happening, though they hark back to the days when only cells derived from embryos were available. An American firm called Advanced Cell Technology (ACT) is using them to treat macular degeneration, a cause of blindness. Last year it reported promising results in two patients and Gary Rabin, the firm’s boss, says tests continue.

Even if this specific approach works, though, it is likely to be overtaken by iPS technology. The Japanese, not surprisingly, are in the lead. Soon, the country’s health ministry is expected to approve the first clinical trial of iPS cells, also for macular degeneration. But ACT is not far behind. It hopes to begin a trial of platelets (blood-cell fragments involved in clotting) made from iPS cells. And other firms want to treat everything from Parkinson’s disease to glaucoma to multiple sclerosis.

Academia is pushing ahead as well. Inspired by Dr Yamanaka’s work, people are looking for other shortcuts to pluripotency. Marius Wernig of Stanford University, for instance, has worked out how to use three proteins to turn connective-tissue cells into neurons. Deepak Srivastava of the University of California, San Francisco, meanwhile, has shown how to convert connective tissue into heart cells.

Other research is going beyond simple cell cultures. In 2011 Yoshiki Sasai of the RIKEN Centre for Developmental Biology, in Kobe, showed how mouse embryonic stem cells, if mixed with a few appropriate growth factors, quickly form a three-dimensional cluster made of the precursor cells to neurons. This cluster then turns into something resembling the back of an eye. Last year Dr Sasai repeated the trick with human cells.

The dream is to make a complex organ from scratch. With this in mind researchers at Wake Forest University in North Carolina have used a three-dimensional printer to produce an artificial kidney using immature kidney cells. But if such organs are to work in people, they will need blood vessels to deliver oxygen and nutrients.

The way to do that might, paradoxically, be for scientists to do less. Instead of making the whole organ in a laboratory, they might create a less-developed form, as Dr Sasai did with his proto-retina, and then leave the rest of the work to the body.

This is what Dr Takebe has done with his liver buds. He coaxed some iPS cells into becoming liver endodermal cells. (The endoderm is one of the three cell layers of which the youngest sort of embryo is composed, and is the layer from which the liver develops.) He then cultured them with two other cell types: endothelial cells, which make up the inner linings of blood vessels, that were derived from umbilical cord; and mesenchymal stem cells, derived from bone marrow, which can differentiate into several kinds of cells, though not as many as pluripotent cells.

Cultures without mesenchymal stem cells failed to form a cluster. Those without endothelial cells failed to create a network of blood vessels. But together, the three types of cell, with little additional prodding, formed a bud within two days.

At six days this bud was expressing genes known to be early markers of the liver. And when Dr Takebe implanted such buds into the brains of mice whose immune systems had been disabled to prevent rejection (he chose the brain because it is easy to fit the cranium with a tiny clear plate, so that you can see what is going on), he observed that they connected with the mouse’s blood system within two days.

After two months the buds not only looked like liver, they acted like it. They produced liver-specific proteins. And if Dr Takebe transplanted them to their host’s abdominal cavity, having first caused the animal’s real liver to fail, they often kept the mouse alive when an animal without the transplant would have died.

Translating this work into a way of growing new livers for people whose old ones have stopped working will take time. But it is a big step forward. After years of promise, regenerative medicine may be coming close to delivering.