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Growing human brain cells in the lab

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Li Gan, Ph.D., wants to find treatments to help patients with Alzheimer’s disease. Like most researchers, she’s hit a few major roadblocks.

When researchers like Dr. Gan find potential new drugs, it's useful to test them on human cells to increase the chances that they will benefit patients. Historically, these tests have been conducted in cancer cells, which often don’t match the biology of human brain cells.

“The problem is that brain cells from actual people don't survive well in a dish, so we need to engineer human cells in the lab,” explained Dr. Gan, senior investigator at the Gladstone Institutes. “But that’s not as simple as it may sound.”

Many scientists use induced pluripotent stem cells (iPSCs) to address this issue. IPSCs are made by reprogramming adult cells to become stem cells, which can then be transformed into any type of cell in the body. Dr. Gan uses iPSCs to produce brain cells, such as neurons or glial cells, because they are relevant to neurodegenerative disease.

Human brain cells derived from iPSCs offer great potential for drug screening. Yet the process for producing them can be complicated, expensive and highly variable. Many of the current methods produce cells that are heterogeneous, or different from one another, and this can lead to inconsistent results in drug screening. In addition, producing a large number of cells is very costly, so it’s difficult to scale up for big experiments.

A new platform developed in Dr. Gan's lab should help scientists overcome these constraints.

“I came across a new method to produce iPSCs that was developed at Stanford,” said Michael Ward, M.D., Ph.D., a former staff scientist in Dr. Gan’s lab who is now an investigator at the National Institutes of Health. “I thought that if our team could find a way to simplify and better control that approach, we might be able to improve the way we engineer human brain cells in the lab.”

Dr. Ward and his colleague, Chao Wang, Ph.D., discovered a way to manipulate the genetic makeup of cells to produce thousands of neurons from a single iPSC. This meant that every engineered brain cell was now identical.

The team further improved the technique to create a simplified, two-step process. This allows scientists to precisely control how many brain cells they produce and makes it easier to replicate their results from one experiment to the next, according to the research team.

Their technique also greatly accelerates the process. While it would normally take several months to produce brain cells, Dr. Gan and her team say they can now engineer large quantities within one or two weeks, and have functionally active neurons within one month.

The researchers realized this new approach had tremendous potential to screen drugs and to study disease mechanisms. To prove it, they tested it in their own research.

They applied their technique to produce human neurons by using iPSCs. Then they developed a drug discovery platform and screened 1,280 compounds. Their goal is to identify the compounds that could lower levels of the protein tau in the brain, which is considered one of the most promising approaches in Alzheimer’s research and could potentially lead to new drugs to treat the disease.

“We showed that we can engineer large quantities of human brain cells that are all the same, while also significantly reducing the costs,” said Dr. Wang. “This means our technology can easily be scaled up and can essentially be used to screen millions of compounds.”

Dr. Gan reported that her team has shared the new method with other academic colleagues, some of whom had no experience with cell culture. So far, she said, they all successfully repeated the process to produce their own cells and facilitate scientific discoveries.

Details of the technique were published October 10 in Stem Cell Reports.

Learn more:

https://gladstone.org/about-us/press-releases/growing-human-brain-cells-lab
DOI: http://dx.doi.org/10.1016/j.stemcr.2017.08.01