Researchers at the Hubrecht Institute and Utrecht University have developed a revolutionary and effective way of introducing molecular tools into cells. According to Dr. Niels Geijsen, who headed the research team, this discovery brings us one step closer to treating genetic diseases:
“The difficulty of treating genetic (inherited) diseases is that we, thus far, are unable to safely transport large therapeutic compounds, for example, proteins, into cells,” explains Geijsen. “ With our new technology, we’ve found that we can do this very efficiently.”
What is the idea behind this study?
Proteins are the workhorses of our cells as they coordinate nearly all biochemical processes in our body with great precision. The administration of specific gene-editing proteins into patient (stem) cells could be an effective way of treating hereditary diseases, but the cell membrane forms an impenetrable barrier that prevents administered proteins from passing through.
Dr. Geijsen and his team have developed a new technology that makes it possible to introduce proteins very efficiently into almost every cell type in the human body.
What did this study show (and how is table salt involved)?
The new technology, called iTOP, activates a back door in a cell, whereby proteins or RNA are taken up from the cell’s surroundings and inserted into the cell. The researchers originally planned to use a cellular pathway that allows toxic proteins of certain bacteria to enter the cell. They hoped that other proteins could be introduced in a similar way, by linking them to a small, harmless part of the toxin.
After nearly a year of experiments, the system finally worked. Surprisingly, the team discovered that the toxin part was not necessary for the protein transport. Instead, they had uncovered a combination of compounds which forces the cell to take up any protein it’s offered.
The main ingredient was sodium chloride, commonly known as table salt. The administered salt mixture extracts water from a cell, and which activates a process called "macropinocytosis"; literally "drinking large mouthfuls of liquid”. Proteins dissolved in the salt mixture are engulfed by the thirsty cells. A second substance in the mixture then causes the release of the proteins inside the cell, where they can do their job.
What does this mean for patients?
The technology is brand new, but the research team who developed it are already thinking about how it might be used. They are keen to investigate how it can be applied to repair dysfunctional genes in patient cells.
One tool that may help, and that the researchers show works very well with iTOP, is the recently discovered CRISPR-Cas9 gene-editing system. CRISPR-Cas9 makes it possible to modify a specific DNA sequence in the genome, yet it has been very difficult to introduce this system efficiently and safely into cells. Geijsen and his team may have found the critical link that can drive CRISPR-Cas9 into the clinic, since iTOP is highly efficient and does not rely on a viral vector.
More about the CRISPR-Cas9 system
Further information and links
The original article is titled “Efficient Intracellular Delivery of Native Proteins” and was published in Cell on 23 April 2015.
The Hubrecht Institute is a EuroStemCell partner and supplied the information on which this research spotlight is based.