Synthetic DNA Designed for Genetic Tracing of Cell Identities Shows Potential for Improved Immunotherapies

All the cells in our body have the same genetic code, but they still differ in terms of their identities, functions, and states. As scientists try to understand infections, inflammations, or cancers, it is important to tell one cell apart from another in real time.

Tailored DNA Tool

At Max Delbrück Center, scientists have created an algorithm that can design tools that reveal the identity and state of cells. The study is led by Dr. Carlos Company, who took the initiative to develop DNA tools that are automated and accessible to other scientists. The findings are reported in the paper "Logical design of synthetic cis-regulatory DNA for genetic tracing of cell identities and state changes."

Dr. Company coded an algorithm that can generate tools to understand basic cellular and disease processes such as cancers, inflammation, and infections. Named "logical design of synthetic cis-regulatory DNA (LSD)," the computer program uses the input of known genes and transcription factors in identifying DNA segments that control the activity of cells under study.

This information is enough to discover functional sequences, so experts will not have to know the precise genetic or molecular reason behind the behavior of a cell. The algorithm allows the researchers to make exact DNA tools for marking and analyzing cells, providing new insights into cellular behaviors. It enables them to examine how cells transform from one type to another.

The computer program looks within the genomes of either humans or mice to spot the areas where transcription factors are more likely to bind. It provides a list of 150 base pair long sequences that are relevant and which act as active promoters and enhancers for cellular conditions.

The tool is innovative since it compiles all the vital instructions that direct cellular changes into a simple synthetic DNA sequence. As a result, studying complex cellular behaviors in cancer research and human development is made more simple. The researchers hope their work will open doors for a more straightforward and scalable way of understanding and manipulating cells.

Harnessing the Potential of DLC

From the generated computer program, scientists can make a tool called "synthetic locus control region" (sLCR), which includes the generated sequence followed by a DNA segment that encodes a fluorescent protein. The sLCRs act like an automated lamp that can be placed inside the cells. This lamp switches on only under the conditions the scientists want to study. Meanwhile, the color of the "lamp" can be changed to match various states of interest, allowing the experts to look under a fluorescence microscope and immediately know the state of each cell from its color.

To validate the utility of the computer program, the research team used the tool to screen for drugs in cells infected with SARS-CoV-2. It was also used to find mechanisms implicated in brain cancers known as glioblastomas, a disease where no single treatment works.

In finding treatment combinations that work for specific cell states in glioblastomas, experts must understand what defines these cell states and see them as they arise.

With immune cells engineered in the lab, scientists can use them as gene therapy for killing cancer. However, not all these cells will work as intended when infused into the patient. Some of the cells will be potent, and some may be in a dysfunctional state. The research team plans to use this system to analyze the behavior of these delicate anti-cancer cell-based therapeutics during manufacturing.