Mini-Brains, Major Capabilities

by Guy McKhann, M.D.

May 31, 2016

This is a column from Dana's print publication, Brain in the News.

Advances in our understanding of the brain and brain diseases are often dependent on advances in technology. We’ve learned more about the clinical aspects of brain diseases in recent years because of advances in imaging. Imaging now allows us to not only see the structure of the brain, but also what parts of the brain are involved in brain functions—what parts of the brain you are using when you read this sentence, and what parts you’d use if you repeated the sentence back to me, for example.

There are many situations in which we would like to model what the human brain does. How does it develop? How does it respond to injury? Will a drug alter disease? We are very limited in what we can do with the living human brain, so for years we have turned to animals, particularly mice and rats. But the transition from findings in a rodent to human application has been very limited. For years, investigators have induced strokes in rats before introducing drugs that successfully reduced the size of the stroke or aided the recovery. And yet, not a single positive approach in rats has led to a successful stroke therapy in humans.

This may all be changing. The new technology is the formation of “mini-brains”: The production of the developing human brain in a dish. This is possible because of recent advances in cellular biology. In all animals, life starts when sperm from a sperm cell inseminates an egg in the ovary. The inseminated egg begins to divide into primitive cells that have the ability to differentiate into any cell in the body. They could produce muscle, brain, heart, or skin. If you remember back about 10 or 15 years, there was much discussion—and hype—surrounding the potential therapeutic benefit of these stem cells. There were also ethical concerns about the need for human embryos at a very early stage of development.

All that changed when investigators asked, “Why can’t we make stem cells from adult cells?” It took a few years, but it is now possible, even routine, to take a mature, developed cell and dedifferentiate it back to a multi-specific stem cell. The usual starting cell, a fibroblast from the skin, is obtained from a tiny bit of skin. The cells are grown in a culture dish. The fibroblasts are then dedifferentiated back to stem cells. These induced stem cells are called induced pluripotent stem cells, abbreviated as iPSCs.

Creating iPSCs from an individual makes several things possible. One can make specific mature cells and put them back in the person who supplied the fibroblasts, eliminating the genetic heterogeneity and tissue rejection that occurs when cells from a different person are introduced. A second opportunity is to compare iPSCs from a normal person with a diseased person to determine the disease-related differences and outline a path to treatment.

With the first half of this problem solved, let’s address the second: taking iPSCs and developing them into brain cells. This also has been done, at several centers in Germany and here in the United States, including at Johns Hopkins. Since I am very familiar with what goes on at my institution, I will focus my discussion on the Hopkins research.

The most exciting part of this research involves creating “mini-brains.” These mini-brains, about the size of the head of a pin, can be used to study the development of the human brain and how development is altered by a virus. Hopkins researchers are currently using mini-brains to study the Zika virus. This study is just the tip of the iceberg. One can think of all kinds of questions that can be asked with this new technology: I will address some of them in future columns. It’s a very exciting time to be involved in brain research!

You can watch a two-minute, lay-friendly video outlining the iPSCs-to-mini-brains process on the Johns Hopkins website.