Cultivator of Brain Parts

An ambitious researcher wrestles with some of the grand challenges of neural development

The lab-grown cortex wasn't perfect, however: it had only four of the cerebral cortex's six cell layers, for example. Sasai thought that a retina — a layered tissue that sprouts from the embryonic brain and contains light-sensing photoreceptors — might be easier to grow. The retina is thinner than the cortex, forms earlier in embryo development and doesn't require a complex vascular system.

To adapt his system to a different type of tissue, Sasai makes minute changes to the culture conditions that nudge the cells down a developmental path. He genetically engineers fluorescent 'reporter' genes into the stem cells so that they are expressed when the cells differentiate into the desired type — in this case, retinal precursor cells — and reveal whether the system is working. “Our success depends on knowing how slight modifications can lead to dramatic change,” he says.

All it took to grow a retina, it turned out, were a few tweaks, such as a reduction in the concentration of growth factors and the addition of a standard cell-culture ingredient called Matrigel. The result closely mimics eye development in the embryo (see 'How to grow an eye'). By the sixth day in culture, the brain balls start sprouting balloon-like growths of retinal cells, which then collapse in on themselves to make the double-walled optic cups. Sasai's team snip them off — “like taking an apple from a tree”, says Sasai — transfer them to a different culture and let them be. Two weeks later, the cups have formed all six layers of the retina, an architecture that resembles the eye of an 8-day-old mouse (which, at that age, is still blind). That the cells could drive themselves through this dramatic biomechanical process without surrounding tissues to support them1 stunned Sasai as much as anyone else. “When I saw it, I thought, 'Oh my god.' Shape, topology and size are all recapitulated,” he says. Carefully explaining the pun to come, he adds: “In English, when you are surprised, you say 'eye-popping' — so we really thought this was eye-popping.”

Reproducing the results with human cells was the obvious, but not simple, next step. Peter Coffey, an ophthalmologist and neuroscientist at University College London, tried following Sasai's recipe to grow optic cups with human cells, and, as Coffey puts it, “failed catastrophically”. Sasai, who reported10 this year that he had accomplished the feat, says that it took careful tweaks to accommodate the sensitivities of human embryonic stem cells. Because these cells grow three times slower than those from mice, for example, Sasai had to start with of 9,000 cells instead of 3,000. Coffey says that his experience made him realize how much expertise has been built up in Sasai's lab. “They've been doing it a long time. Good on 'em,” he says, with an air of good-natured jealousy.

All eyes
All this will not create eyes that can be plugged into an eye socket like a light bulb into a lamp. Even if Sasai could get his optic cups to develop into mature retinas, researchers have little idea about how to wire a transplanted retina up to the brain.

What the work does offer is a potentially abundant source of pure, dense, well-organized photoreceptors, the developmental stage of which can be precisely selected — something that has been difficult to achieve in standard two-dimensional culture. Eventually, Sasai hopes, his optic cups will provide sheets of photoreceptors that can be inserted into a retina damaged by conditions such as retinitis pigmentosa or macular degeneration. Sasai demonstrates the procedure by grabbing a stack of papers to stand in for the retinal layers and then slipping one sheet between the others.

But linking the transplanted photoreceptors with the rest of the retina and with the brain will not be easy, as researchers working on eye stem-cell technologies have found. Robert Lanza, chief scientific officer of the stem-cell therapy company Advanced Cell Technology in Santa Monica, California, is sceptical. “I don't think we're anywhere near when we get those cells to connect up in any meaningful way,” he says.

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