Ablation in medicine means to remove tissue by various means, such as cutting, chipping or vaporizing, to eliminate a threat to health. Cellular ablation is a more particular endeavor: Cells are selectively destroyed to better understand their lineage and function.
Researchers have some clever tools to do this. A laser, for example, can focus upon a single cell in Caenorhabditis elegans, a tiny worm and proven model organism. Or genetically coded reagents, such as enzymes or cytotoxic molecules, can be introduced into targeted cells to induce apoptosis or programmed cell death.
The problem with the latter approach, which has been used in organisms other than C. elegans, is that chemical reagents may accumulate in tissues other than the targeted cells, causing non-specific toxicity. In other words, healthy cells near the target can also die.
In a paper published online this week in the Proceedings of the National Academy of Sciences, Yishi Jin, PhD, a professor in the division of biological sciences and Howard Hughes Medical Institute investigator, and Roger Tsien, PhD, professor of pharmacology, chemistry and biochemistry Howard Hughes Medical Institute investigator, and Nobel laureate describe, with colleagues, using a tiny, light-activated molecule to effectively kill single neurons in a nematode without any apparent collateral effect.
The molecule is called a mini-singlet oxygen generator or miniSOG. It’s a radically re-engineered light-absorbing protein from the cress plant Arabidopsis thaliana that, when exposed to blue light, produces abundant quantities of singlet oxygen. The researchers in Jin’s lab targeted the expression of miniSOG to mitochondria, and observed that the expressing cells die quickly upon blue light illumination, without affecting neighboring tissues.
“We believe that singlet oxygen generated by miniSOG (genetically introduced into the mitochondria of the targeted neuron) destroys the integrity of the mitochondria, which releases toxic molecules that lead to the death of the cell,” said Jin. “The dead neuron is then cleared away by nearby cells, most likely through phagocytosis.”
While the findings may be a boon to basic research, Tsien said they are unlikely to have direct value for developing human treatments because the method requires gene therapy, which is not yet practical enough.
“Plus it needs blue light, which doesn’t penetrate very far through organisms as thick as ourselves. However, we are separately working on synthetic injectable molecules (not minSOG) that would home in on cancer cells and kill them with red or near-infrared light, which penetrate mammalian tissues much better than blue light. But even red or near-infrared would mostly have to be applied by endoscopes or during surgery.”