One of the most amazing things to happen in biology in the last couple of years is cellular reprogramming. We learned how to convert one type of cell into another.

In 2006, Shinya Yamanaka made a groundbreaking discovery that would win him the Nobel Prize in Physiology or Medicine just six years later: he found a new way to ‘reprogram’ adult, specialized cells to turn them into stem cells. These laboratory-grown stem cells are pluripotent — meaning they can make any type of cell in the body — and are called induced pluripotent stem cells, or iPS cells. Before Yamanaka, only embryonic stem cells were pluripotent.

Now, in a major leap for regenerative medicine, engineers at MIT have developed a method to transform skin cells directly into neurons, bypassing the need for an intermediate stem cell stage. This streamlined process could pave the way for generating large quantities of motor neurons, with immediate benefits for treating spinal cord injuries and diseases like ALS.

“We were able to get to yields where we could ask questions about whether these cells can be viable candidates for the cell replacement therapies, which we hope they could be,” said MIT Professor Katie Galloway. “That’s where these types of reprogramming technologies can take us.”

From Skin to Neurons: Straight to the Point

For nearly two decades since they were introduced, scientists have relied on a laborious method to induce pluripotency. In order to turn adult cells back into pluripotent stem cells, scientists typically use viruses to insert four genes — Sox2, Oct4, Klf4, and cMyc — into the cells. While effective, this approach is time-consuming and often inefficient, with many cells failing to fully mature.

Galloway’s team sought to cut out the middleman. Instead of guiding skin cells through the iPSC stage, they aimed to convert them directly into neurons. It’s not the first time someone has tried this. But previous attempts at direct conversion had been plagued by low yields, with fewer than 1 percent of cells successfully transforming.

The MIT researchers cracked the code by identifying a precise combination of three transcription factors — NGN2, ISL1, and LHX3. These efficiently reprogram mouse skin cells into motor neurons. They also introduced two additional genes, p53DD and a mutated version of HRAS, to drive the skin cells into a highly proliferative state before conversion. The necessary genes were introduced in the cells using a retrovirus. This tweak dramatically increased the yield, producing more than 10 neurons from a single skin cell (around 1,100 percent yield).

“Hyperproliferative cells are more receptive,” Galloway explains. “It’s like they’ve been potentiated for conversion, and then they become much more receptive to the levels of the transcription factors.”

New and Integrated Neurons

In collaboration with Boston University, the team implanted these neurons into the brains of mice, targeting the striatum, a region involved in motor control. After two weeks, many of the neurons had survived and appeared to integrate with the host tissue, forming connections with other brain cells.

“When grown in a dish, these cells showed measurable electrical activity and calcium signaling, suggesting the ability to communicate with other neurons,” Galloway says.

The next step is to explore whether these neurons can be implanted into the spinal cord, where they could potentially repair damage caused by injury or disease.

The team also adapted the method for human cells, though with lower efficiency — somewhere between just 10 and 30 percent. While the process takes about five weeks, it is still faster than the traditional iPSC route.

A New Era for Cell Therapy

By simplifying the process of generating neurons, the MIT team has opened the door to producing large quantities of cells for therapeutic use. This could be a game-changer for conditions like ALS — a fatal motor neuron disease — where clinical trials using iPSC-derived neurons are already underway. Theoretical physicist Stephen Hawking and Baseball great Lou Gehrig had ALS.

“Expanding the number of cells available for such treatments could make it easier to test and develop them for more widespread use in humans,” Galloway says.

While challenges remain, particularly in improving the efficiency of human cell conversion, the work represents a significant stride toward making cell replacement therapies a reality.

The findings appeared in the journal Cell Systems.