A New Method for Untangling DNA is Helping Scientists Change a Cell’s Identity

The Context: Stem cells are advantageous for disease research because of their ability to become any type of cell in the body, allowing scientists to see exactly how diseased cells dysfunction and gain insight into the biology of individuals and groups. Making stem cells and turning them into other cell types requires a process called reprogramming, in which a cell’s identity is switched (for example, a blood cell becomes a neuron, or a liver cell). To reprogram a cell, researchers must access the cell’s DNA, but this has traditionally been difficult because DNA will tend to resist uncoiling from its double helix shape, allowing for efficient reprogramming just 1% of the time.

The Study: Using a special combination of enzymes, a new DNA-unravelling method is allowing reprogramming efficiency to approach nearly 100%. The method was invented by NYSCF – Robertson Stem Cell Investigator and Assistant Professor of Stem Cell Biology at the University of Southern California (USC) Dr. Justin Ichida and appears in Cell Stem Cell.

The Importance: The new technique improves upon previous reprogramming methods, allowing scientists to more efficiently create patient-specific, disease-relevant cell types for research and therapy.

 The identity of our cells determines their function: heart cells beat, liver cells produce insulin, immune cells fight invaders, etc. The crux of stem cell research is to change a cell’s identity (from a stem cell to a specialized cell type) to understand how disease affects cellular function. Doing so opens the door for in-depth study of the root causes of disease, drug discovery, and regenerative medicine. However, all of this relies on a process called reprogramming, in which scientists turn one cell type into another.

Many efforts, such as NYSCF’s technology and automation processes, have improved and scaled up the reprogramming process so that stem cell research is more accessible, but reprogramming efficiency is still lower than we’d like it to be. A big part of this is because reprogramming requires accessing a cell’s DNA, which can be tricky.

A new study in Cell Stem Cell by NYSCF – Robertson Stem Cell Investigator and Assistant Professor of Stem Cell Biology at the University of Southern California (USC) Justin Ichida, PhD, finds a more efficient method for creating personalized, disease-affected cells types by improving how we access their DNA.

To reprogram a cell, the researchers must unravel a cell’s DNA from its double helix shape. The problem is that DNA will try to resist this interference, so unraveling methods are typically only successful about 1% of the time.

“Think of it as a phone cord, which is coiled to begin with, then gets more coils and knots when something is trying to harm it,” says Dr. Ichida in an article from USC.

Dr. Ichida’s new technique uses a cocktail of enzymes to relax DNA— sort of like how conditioner untangles strands of hair. This cocktail provided easier access to DNA, making it easier for cells to ramp up both gene expression and their own proliferation. These ‘hyperproliferating’ and ‘hypertranscribing’ cells can be reprogrammed far more easily. In fact, when the team reprogrammed fibroblasts to neurons, they found that their new method had nearly 100% efficiency.

“This is a strategy for greatly improving our ability to perform cellular reprogramming, which could enable the regeneration of lost tissues and the study of diseases that cannot be biopsied from living patients today,” said Dr. Ichida.

Dr. Ichida says that his technique should also more closely retain the ‘age’ of the cells than traditional stem cell reprogramming methods, which may facilitate research into age-related diseases.

“The key is to understand development of disease at a cellular level and how disease affects organs,” explained Dr. Ichida. “This is something you can do with stem cells, but in this case, it skips a stem cell state. That’s important because stem cells reset epigenetics and make new, young cells, but this method allows you to get adult cells of same age to better study diseases in aged individuals, which is important as the elderly suffer more diseases.”

Journal Article:

Mitigating Antagonism between Transcription and Proliferation Allows Near-Deterministic Cellular Reprogramming
Kimberley N. Babos, Kate E. Galloway, Kassandra Kisler, Madison Zitting, Yichen Li, Yingxiao Shi, Brooke Quintino, Robert H. Chow, Berislav V. Zlokovic, Justin K. Ichida. Cell Stem Cell. 2019. DOI: https://doi.org/10.1016/j.stem.2019.08.005