Bioelectric Head Regeneration

Wouldn’t it be great if we could regenerate any organ including our brain? Some animals, like the planarian flatworm, have this incredible capability. Studying what enables these fascinating creatures to do this might give us insights into how we might someday come closer to accomplishing regenerative feats in medicine.

Although flatworms look very different from people, these animals have a number of things in common with us. Further, they share more genes with vertebrates than many other animals that are commonly studied in research, like fruit flies and nematodes. But how can we apply information from planarians to people?

Although all of the cells in your body generally have the same DNA, they do not all behave the same way For example, the cells in your eye are making and using different protein machinery than the cells in your skin, enabling them to look and function very differently from one another. Proteins are molecular machines encoded for in DNA that enable cells to carry out their different functions. But what controls when and what proteins are made from the DNA? More importantly, how can we control it to enable the precise regrowth of organs?

There are multiple ways that we might be able to change or control protein production. We could change the actual DNA sequence, which has its difficulties. But a less invasive alternative could be chemical genetics, which refers to studies where drugs or potential medicines are tested for their ability to alter protein activity. It turns out that planarians are great for studying the effects of chemicals on regeneration. 

An intriguing research study explored an exciting mechanism for controlling regeneration called bioelectricity. Some biologically active molecules possess a positive or negative charge. These ions include sodium, potassium, and calcium, for example. Ion concentrations can be different inside and outside the cell, generating a charge imbalance. The imbalance of charge in turn creates an electric gradient. Much in the same way an apple falls down to the ground because it is attracted by gravity, ions can pulled in a certain direction by an electric gradient. The cell can control this gradient by allowing different numbers of ions in and out through channels and pumps at the surface of the cell. Unlike the type of electrical signals observed in brain and heart cells that are very rapid, these bioelectric gradients are present in all cells, and change very slowly. Surprisingly, a growing number of research trials have shown that bioelectric signals can control cell development and function, but the mechanism of how this occurred was not well understood.

The researchers of the study discussed here used a chemical genetics approach to change bioelectric signals by applying chemicals that affected ion channels. They performed a screen, or a test of multiple chemicals, to identify which ones caused a change in regenerative capability of the planarians. The researchers found that a drug that inhibited the activity of a particular ion pump (H+/K+ ATPase) that transports hydrogen and potassium ions led to a complete stoppage of head formation in planarians that had been cut in half. The result was headless worms that had regenerated a second tail instead of a head. However, the researchers discovered that the presence of brain tissue could override the effect of this ion pump inhibition and allow head formation to proceed normally. This suggested that the process of head regeneration was much more complex than previously thought and involved a finely-tuned interplay between different components.

Further investigation was done using a voltage-reporting dye called DiBAC which can be used to actually see bioelectric fields. This fluorescent dye is brighter in areas that are more positively charged, a state called “depolarized” and dimmer in areas of more negative charge, a state called “hyperpolarized”. This dye revealed that as planarians regenerate their head, they have a head-to-tail voltage gradient, with more depolarized cells towards the area of head regeneration. However, when the H+/K+ ion channel was inhibited, this depolarization was lost, and the regenerating worms were significantly more hyperpolarized than normal worms. The researchers then hypothesized that it wasn’t just this specific ion channel that was needed for head regeneration. Rather, the bioelectric field gradient created by the ions it transported was the key factor in regenerative ability.

To test this theory, the researchers manipulated the external concentration of potassium ions and found that head regeneration could be rescued even when the ion channel in question was inhibited. But these bioelectric voltage gradients aren’t necessarily created just by one type of ion like potassium. Rather, they result from the balance of many types of ions like sodium and chloride. They discovered that opening a particular chloride channel (GluCl) with an activator chemical called Ivermectin resulted in the formation of a second head in worms that had both an amputated head and tail, resulting in two-headed worms over 90% of the time. The regions that formed a new head were depolarized compared to the rest of the tissue.

These findings suggested that changes in bioelectricity due to ion concentrations are crucial for the planarian’s incredible ability to regenerate. Further, manipulating this bioelectric field with drugs that disrupt the function of ion channels and pumps could lead to significant defects in regeneration. But ion channels are not unique to planarian worms. In humans, disruptions in ion transport channels, called “channelopathies” can cause many different diseases, including cystic fibrosis, epilepsy and neurological disorders, cardiac malfunction, and kidney disease. Developing pharmacological inhibitors or activators of ion channels to control ion flux and correct these disruptions could offer an exciting approach to treating such diseases. Still, it’s unclear exactly how bioelectric fields influence human biology, and whether they could be harnessed for regenerative potential in people. However, unlocking the secrets of planarian regeneration might uncover surprising new avenues of research. 

Reference for the paper discussed in this article:

Beane, Wendy S., et al. "A chemical genetics approach reveals H, K-ATPase-mediated membrane voltage is required for planarian head regeneration." Chemistry & biology 18.1 (2011): 77-89.