Imagine if scientists could use AI to manipulate the genetic makeup of a single type of cell without affecting other cells in the body.
A new technological method appears to be opening a way to allow precise activation—or precise repression—of genes in specific tissues.
This could revolutionize gene therapy and biotechnology, said researchers from The Jackson Laboratory (JAX), Harvard University, Yale University, and the Broad Institute of the Massachusetts Institute of Technology in a new report.
JAX is a leading biomedical research institution in Bar Harbor, Maine, with the mission of discovering genomic solutions for diseases, including how to prevent and treat cancers.
The new finding “creates the opportunity for us to turn the expression of a gene up or down in just one tissue without affecting the rest of the body,” said senior co-author Ryan Tewhey, PhD, about the JAX report, which was published in an Oct. 23 advanced online issue of Nature.
“Although every cell in an organism contains the same genes, not all the genes are needed in every cell, or at all times,” the report said.
The core of the report revolves around the human body’s natural gatekeepers called cis-regulatory elements (CREs).
“CREs themselves are not part of genes, but are separate, regulatory DNA sequences—often located near the genes they control,” the JAX release explained. “CREs help ensure that genes needed in the brain are not used by skin cells” or that genes needed for toddler development “are not activated in adults,” it added.
Tewhey and his colleagues broke new ground by designing synthetic CREs. Senior co-author Dr. Pardis Sabeti, a core institute member at the Broad Institute and professor at Harvard, developed a platform called CODA (Computational Optimization of DNA Activity). It “used their AI model to efficiently design thousands of completely new CREs with requested characteristics, like activating a particular gene in human liver cells but not activating the same gene in human blood or brain cells,” the JAX report said.
Tewhey, an associate professor at JAX, is excited that these “synthetically designed” switches “show remarkable specificity to the target cell type they were designed for.”
The group tested several synthetic CRE sequences in zebrafish and mice, “with good results,” the Jax release said. “One CRE, for instance, was able to activate a fluorescent protein in developing zebrafish livers but not in any other areas of the fish.”
There have been advances in gene editing in living cells. But prior to these researchers’ breakthrough, altering certain genes within targeted cell types or selected tissues had been difficult. This is because computer models were incapable of searching every possible combination of sequences in a typical human CRE, the JAX report said.
“[W]ith no straightforward rules that control what each CRE does, this limits our ability to design gene therapies that only affect certain cell types in the human body,” said Rodrigo Castro, PhD, a computational scientist in the Tewhey lab at JAX and co-first author of the new paper.
“This project essentially asks the question: ‘Can we learn to read and write the code of these regulatory elements?’” said Steven Reilly, PhD, assistant professor of genetics at Yale and one of the senior authors of the study. “If we think about it in terms of language, the grammar and syntax of these elements is poorly understood. And so, we tried to build machine learning methods that could learn a more complex code than we could do on our own.”
"Natural CREs, while plentiful, represent a tiny fraction of possible genetic elements and are constrained in their function by natural selection," said study co-first author Sager Gosai, PhD, a postdoctoral fellow in Sabeti's lab.
"These AI tools have immense potential for designing genetic switches that precisely tune gene expression for novel applications, such as biomanufacturing and therapeutics, that lie outside the scope of evolutionary pressures," Gosai said.
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