Originally published 2021-09-13.
In August 2021 a team at University Hospital Düsseldorf in Germany reported that brain organoids, pea-sized clusters of human nerve tissue grown from stem cells, had spontaneously formed a pair of primitive eye structures called optic cups. The cups contained several kinds of retinal cells that reacted to light and sent connections into the neighbouring brain tissue.
That does not mean scientists grew a seeing brain in a dish. The structures are tiny, have no blood supply and nothing resembling thoughts or perception. What the work does offer is a new way to watch how the eye and brain wire themselves together in the earliest weeks of human development, and a possible route to studying inherited eye diseases in the lab.
What the Düsseldorf team found
The study, published in the journal Cell Stem Cell on 17 August 2021 under the title "Human brain organoids assemble functionally integrated bilateral optic vesicles", was led by Elke Gabriel with senior author Jay Gopalakrishnan, a cell biologist who heads a research group at the Düsseldorf hospital.
The researchers grew 314 organoids in 16 separate batches, using stem cells from four different donors. Roughly three-quarters of them (the press release gives 72 percent) developed optic cups, and in many cases the cups appeared symmetrically on both sides, much as the eyes do in an embryo.
The timeline also mirrored natural development. Optic cups began to emerge at around day 30 of growth and were clearly visible by day 50, a pace the authors compare with the formation of the retina in a human embryo.
Inside the cups the team identified a range of retinal cell types, as well as lens and corneal tissue. The retinal cells formed electrically active networks that responded to light, and nerve fibres extended from them into the brain tissue. According to the authors, that kind of retina-to-brain connection had not been shown before in a lab-grown system.
What a brain organoid actually is
A brain organoid, sometimes called a cerebral organoid or mini-brain, is a three-dimensional ball of nerve tissue grown from pluripotent stem cells. These cells can become almost any cell type in the body. Many labs now use induced pluripotent stem cells, which are made by reprogramming ordinary adult cells such as skin or blood cells, so no embryos are needed.
The method most labs build on was described in Nature in 2013 by Madeline Lancaster and colleagues at the Institute of Molecular Biotechnology in Vienna. Stem cells are first coaxed into a clump, guided towards nerve tissue and then grown in a supporting gel. Chemical signals added to the culture push development towards particular brain regions.
The result resembles parts of a developing fetal brain, with layers and cell types that appear in the right order, but it is far simpler than a real brain. Organoids have no blood vessels, so nutrients struggle to reach the centre, which has often died off as the ball grows. They also vary considerably from one culture to the next, and creating and analysing a single one can take months.
Why eyes grew from brain tissue
It may sound strange that eyes would sprout from a brain, but that is exactly how they develop in an embryo. The retina is technically part of the central nervous system. Early in development, a pouch called the optic vesicle bulges out from the forebrain on each side, then folds inward to form the optic cup that becomes the retina. The stalk that connects it to the brain later carries the optic nerve.
Earlier research had already grown retinal organoids, but these were pure retina, grown on their own. The Düsseldorf team chose not to force their cells too quickly down a strictly neural path and added a form of vitamin A, retinol acetate, to the growth medium. That gave the tissue room to develop both brain and eye structures together, in their natural relationship.
Gopalakrishnan summed up the appeal: These organoids can help to study brain-eye interactions during embryo development
, he said, according to the hospital's press material reported by ScienceAlert.
What this research could be used for
The most immediate value is as a window into development. Scientists cannot easily watch a human retina connect to the brain in the first two months of pregnancy, but they can observe it in an organoid, test what happens when a gene is switched off, and see where the process goes wrong.
That matters for congenital retinal disorders, eye conditions that are present from birth and often linked to faulty development. Because organoids can be grown from a particular patient's cells, researchers hope to recreate an individual's condition in the lab and test potential treatments on it before trying them in a person.
The paper also points to a longer-term goal: producing patient-matched retinal cells, including sheets of retinal pigment epithelium, the layer that supports the light-sensing cells, for future transplant therapies. That is still at the research stage. Even the authors noted that keeping the optic cups alive and functioning for longer periods is a challenge they have yet to solve.
Common misunderstandings
"Scientists grew a brain that can see"
No. The cells responded to light in the way photoreceptor-like cells do, which is a chemical and electrical reaction, not vision. Seeing requires a complete eye with a focusing lens, an optic nerve and visual centres in a mature brain that can interpret the signals. None of that exists in an organoid.
"Mini-brains might be conscious"
There is no evidence of that. Organoids are millimetres across and contain a small fraction of the cells of a real brain, without the structure, blood supply or sensory input a working brain needs. Ethicists still take the question seriously for the future, and a 2018 symposium at the University of Oxford brought scientists, philosophers and lawyers together to discuss where limits should lie, but current organoids are generally considered far too simple for experience of any kind.
"This research uses embryos"
The Düsseldorf study used induced pluripotent stem cells from adult donors, not cells taken from embryos. Some people still object to stem cell research in principle, often on religious grounds, while others see reprogrammed adult cells as a way around the most serious ethical concerns.
Where organoid research goes next
Labs around the world are working on the weaknesses that limit today's organoids. Some grow them in fluid-filled devices that improve the flow of nutrients, others try to add blood vessel cells or combine organoids from different brain regions into "assembloids" that interact. Transplanting human organoids into animals, which some groups have done with rats, raises fresh ethical questions of its own.
The optic cup study is one step in that wider effort. It shows that, given the right conditions, human stem cells can organise themselves into surprisingly complex structures that follow the same order of events as natural development. For anyone living with an inherited eye condition, the hope is that a better understanding of how the eye forms will one day lead to better ways to repair it.
Sources: EurekAlert!: Cell Press release on Gabriel et al., Cell Stem Cell (2021); ScienceAlert (Michelle Starr); Wikipedia: Cerebral organoid.
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