How brain organoids are transforming research

Organoids including brain organoids are an exciting, relatively new area of research. This technology is having a powerful impact on biomedical science, which is the focus of today’s post.

What’s in this post

Definition of organoids | Brain organoids | Challenges for mini-brains | Cutting edge cerebral organoids | References

Definition of organoids and brain organoids

We define organoids as miniature organs, including human organs, derived from stem cells. For that reason, more simply we sometimes call them mini-X, where the X stands for the specific organs.

For example, brain organoids are sometimes called mini-brains.

It’s important to stress that organoids are generally just lab-grown approximations of usually underdeveloped parts of organs. Not the whole organ. For that reason, even though we biologists sometimes use the “mini-brain” moniker, it would be more precise to say miniature model of a portion of a partially developed human brain. That’s harder to say though.

Researchers use pluripotent stem cells to grow brain organoids, which in some cases go by the more technical name “cerebral organoids.”

In my own lab here at UC Davis School of Medicine we have been doing human brain organoid research for several years. We make them from human induced pluripotent stem cells or iPS cells.

Human brain organoids Knoepfler Lab
Human brain organoids. From top left clockwise. Organoid section stained for indicated markers. Next is an H&E stained organoid section that looks like a smiling head. Bottom row. Two whole brain organoids, unstained. Knoepfler Lab images.

Some of the first organoids were mini versions of gut. Under carefully defined conditions stem cells or gut cells could organize into 3D structures that resembled real gut. I’ve included a beautiful stained gut organoid picture below.

More broadly, it turns out you can make organoid versions of just about any tissue.

While you also can make organoids from just about any species, I find the human organoid work to be the most exciting. There’s great translational potential.

gut organoid
“Constellation of intestinal organoids” by Ilya Lukonin, Friedrich Miescher Institute for Biomedical Research. “Confocal microscopy images of intestinal organoids stained for nuclei (DAPI, blue), proliferating cells(ki67, red) and nuclear lamina protein Lamin A/C (green).” Creative Commons image. 

Brain organoids

Brain organoids are specifically small models of the parts of the developing human brain. They often measure just a few millimeters.

We use a version of the protocol first developed by pioneering organoid researcher Madeline LancasterA big thank you to her for generosity in helping my lab to get organoids going.

In this technique we first differentiate iPS cells in a general way into something called embryoid bodies or EBs. The EBs resemble little blobs of disorganized embryonic tissue. They have the gene expression signatures of some early embryonic tissues too.

We then change the growth media for the EBs to a neural-induction cocktail. This switch together with growing the cellular globs in matrigel pushes them down a brain development-like pathway. We have to work to keep them happy as they continue to grow. For this reason, they spend their time in flasks where the nutrient-rich media sloshes around. This movement helps keep nutrients and oxygen available.

Challenges for mini-brain work

Size. Organoid work has several limitations. First, there is a size limitation. As the organoids grow, a bit of the interior tissue often dies due to lack of oxygen and nutrients. This roadblock could be overcome by integrating blood vessels into the organoids. Some research along these lines has been reported. While there would be no blood flow, it’s possible that the growth media could move through the vasculature to help keep the organoid more fully alive and growing.

Limited anatomy. Most brain cerebral organoids only reflect parts of the brain. For instance, such organoids generally do not have cells representing other parts of the brain. More recent organoid work has produced structures that resemble the mid or hindbrain. Generating brain organoids with a full representation of different key brain regions is going to be difficult, but it’s doable and important.

Immaturity. Mini-brains also tend to reflect an immature developmental state. In this sense, they are more akin to fetal brain. As a result, mini-brains also are not particularly functional. Some researchers have reported electrical activity in organoids but it is disorganized and fairly basic in nature. In addition, other factors probably contribute to the relative lack of functionality as well.

brain organoids eyes
Brain organoids with primitive eye like structures. ” 60-day-old organoids with bilaterally symmetric pigmented optic vesicles (i–v). Insets in (ii) show individual pigmented regions. Scale bar, 1 mm. n ≥ 32 organoids from ≥ 3 batches. Cell lines IMR-90 (i and ii), F13535.1 (iii + v), and GM25256 (iv).”

Cutting edge organoid work

How about human brain organoids with eyes? Yes, it’s been done in a primitive sense. Researchers recently made mini brains with primitive eye-like structures. See image above.

Other research by Lancaster has produced organoids that make cerebral spinal fluid-like secretions.

One of the coolest recent organoid types produced is venom glands from snakes. Such lab-made snake venom gland organoids can be used in research. The venom itself can be useful indirectly for helping with treatments for snake bites.

Some researchers have made tear-duct organoids that produce actual human tears. This fluid could potentially be helpful for research and for those with dry eyes.

Organoids are also useful drug screening and disease modeling.

Looking to the future, I imagine much more organoid research pushing the limits of imagination.

As to the possible worry over “thinking” brain organoids, I’m less concerned about that idea than I was a few years back.  I’m not sure scientists will ever produce mini-brains that have anything remotely like complex fetal human neural activity. We’ll have to see as this field continues to rapidly advance.

References

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