Since the landmark discovery that a bacterial defense mechanism could be repurposed into programmable “molecular scissors,” CRISPR-Cas9 gene-editing technology has undergone a major evolution. Over several iterations, scientists have tailored this tool—which made simple double-stranded cuts in DNA—into a high-precision instrument capable of single-amino acid edits. The latest advancements include revolutionizing this technology with artificial intelligence (AI).
This decade-plus journey moved from fundamental microbiology to the clinic, where it now delivers bespoke, life-saving therapies for cancers, rare diseases, and more. In honor of The Scientist’s 40th anniversary, we look back at our coverage of CRISPR-based gene editing technologies through the years.
2013: CRISPR Discovery and Its Potential to Treat Diseases
Max Planck Institute for Infection Biology microbiologist Emmanuelle Charpentier and University of California (UC), Berkeley biochemist Jennifer Doudna’s seminal work in 2012 demonstrated that the bacterial Cas9 enzyme could be programmed with synthetic guide RNAs to introduce cuts at specific locations in the DNA. Shortly after this, research teams, led independently by Jinsong Li, a biochemist at the Shanghai Institute for Biological Sciences, and Hans Clevers, a stem cell researcher at the Hubrecht Institute, took this system to mammalian models. Li and his team used CRISPR-Cas9 to replace a single base pair mutation that causes cataracts in mice, and Clevers and his team used CRISPR-Cas9 to correct a defect associated with cystic fibrosis in human stem cells. These foundational studies highlighted that a complex microbial immune mechanism could be adapted into a versatile tool with the theoretical potential to cure genetic diseases in humans.
2014: Modifying CRISPR to Turn Genes On
The first major diversification of the CRISPR toolkit arrived with the development of "dead" Cas9 (dCas9), a version of the enzyme modified so it could no longer cut DNA. Then, Feng Zhang, a biochemist at the Broad Institute of MIT and Harvard and his colleagues tweaked the Cas9 enzyme so that it could upregulate any gene of interest, even those that had resisted previous attempts using CRISPR-Cas. Manipulating the expression of genes is particularly useful for studying their functions, underscoring the importance of re-engineering the CRISPR-Cas9 system to induce gene expression.
2016: A CRISPR-Based Technique Edits Genes Without Cutting the DNA
In a significant leap for precision, Broad Institute molecular biologist and biochemist David Liu and his team introduced base editing. This technique could chemically convert one DNA base into another without breaking the DNA backbone. The editors introduced by Liu and his team could permanently and efficiently convert cytosine (C) to uracil (U) bases with low error rates in human and mouse cell lines. By avoiding the double-strand breaks introduced by traditional CRISPR-Cas9 tools, base editing significantly reduced the risk of random, off-target insertions or deletions that often occur during the natural DNA repair process of gene editing. This was a landmark step toward applying gene editing as a therapy for genetic diseases that need to swap bases.
2016: World’s First CRISPR Clinical Trial
The theoretical became reality when a team in China, performed the world’s first human trial involving CRISPR-edited cells. Sichuan University oncologist Lu You’s team isolated the recipient’s immune cells and used CRISPR-Cas9 to disable the gene encoding programmed cell death protein 1, an immune checkpoint protein that cancer cells hijack for proliferation. The researchers injected these edited immune cells back into the patient and intended to test the same method on nine other patients. This trial marked the official entry of CRISPR into the arena of experimental medicine, setting the stage for global efforts to harness gene editing for immunotherapy and beyond.
2016: The CRISPR Patent Battle
As advancements in CRISPR stood to change the way scientists edited DNA, the technology’s commercial value skyrocketed. This triggered a high-stakes legal fight over the intellectual property rights for CRISPR gene-editing technology between the UC Berkeley, and the Broad Institute. The legal battle centered on who held the right to use CRISPR in eukaryotic cells. While Doudna’s team from UC Berkeley filed a provisional patent application before Zhang’s team from the Broad Institute, they did not go into detail about how they would use CRISPR in eukaryotic cells, unlike Zhang, whose patent was specifically for using CRISPR in eukaryotic cells. These hearings would ensue for almost another decade, shaping the biotech landscape and determining how the technology would be licensed.
2018: The CRISPR Babies Controversy
He Jiankui, a researcher at the Southern University of Science and Technology in China, announced the birth of CRISPR-edited babies in a series of videos, plunging the scientific community into a deep ethical crisis. He used CRISPR-Cas9 to disable the CCR5 gene—which encodes a receptor allowing the human immunodeficiency virus (HIV) to enter the cells—in embryos to confer them resistant to HIV. This move sparked outrage and condemnation from scientists all over the world, who slammed the action as medically unnecessary, technically flawed, and a violation of ethical norms. This incident triggered calls for much stricter oversight on experiments involving human embryos.
2019: Prime Editing: Search and Replace
Even as CRISPR-Cas9 ushered in a new era of gene editing, its clinical applications remained limited due to its off-target effects that could introduce cuts at unintended sections in the DNA. While base editing solved this problem, it still remained imprecise. Building on CRISPR and base editing, Broad Institute scientists Andrew Anzalone and Liu sought to cut only one DNA strand. The outcome, called prime editing, offered a level of precision that earlier tools could not match: It was capable of performing insertions, deletions, and all 12 types of point mutations without requiring double-strand breaks or donor DNA in human and mouse cells. By combining a modified Cas9 enzyme that nicks only one strand of DNA and a reverse transcriptase enzyme that can generate new DNA by copying an RNA template, prime editing expanded the range of genetic corrections possible.
2020: CRISPR Earns Chemistry Nobel
Just eight years after their initial discovery, Doudna and Charpentier won the Nobel Prize in Chemistry for reprogramming CRISPR, a bacterial immune response, into one of the most popular molecular biology tools. This marked one of the fastest recognitions in the prize’s history. The Nobel Committee recognized the duo for their “development of a method for genome editing,” noting that CRISPR has potential applications in treating and curing genetic diseases, fighting cancers, as well as impacting other fields such as agriculture.
2025: Baby KJ’s Bespoke Therapy
Scientists scaled new heights in utilizing gene therapy for treating Baby KJ, an infant diagnosed with an enzyme deficiency that prevented his body from clearing ammonia. Within a record timeline of six months, multiple teams collaborated to use prime editing to treat KJ. Kiran Musunuru, who studies the genetics of cardiovascular and metabolic diseases at the University of Pennsylvania joined forces with UC Berkeley scientists Petros Giannikopoulos and Fyodor Urnov to correct the genetic mutation that KJ carried. This first-ever personalized gene therapy to treat an infant with a genetic disorder would become a milestone in “N-of-1” medicine, offering a roadmap for treating ultra-rare diseases that are often ignored by traditional pharmaceutical companies.
2025: CRISPR-GPT and the AI Revolution
Researchers from Stanford University, Princeton University, and UC Berkeley teamed up with Google DeepMind to create CRISPR-GPT, an AI tool that automates the complex design of CRISPR experiments. This large language model uses text-based input data to guide researchers through every aspect of CRISPR editing from start to finish in as little as one day. The AI tool helps scientists generate the perfect guide RNA, predict how a cell will repair itself, and troubleshoot experiments, allowing first-time researchers to achieve up to 90 percent editing efficiency. The synergy between AI and CRISPR can help scientists optimize their protocols even before stepping in to do the experiments.
