Redefining genetic potential

In 2022, Alyssa Tapley was 13, grappling with T-cell leukemia, and facing a bleak outlook after conventional therapies failed to enhance her situation. Subsequently, a clinical trial employing a pioneering gene-editing innovation known as base editing eliminated her cancer. This represented a significant advancement for the scientific community — Tapley’s treatment was the first made possible by base editing — serving as a lifeline for her.

“Now, 2½ years later, I’m 16, preparing for exams, spending time with my family, bickering with my brother, and engaging in all the activities I believed I would never partake in,” Tapley communicated to the audience at the 2025 Breakthrough Prize ceremony on April 5. The awards, which recognized multiple Harvard researchers this year, acknowledge accomplishments in physics, life sciences, and mathematics.

The innovator behind the technology that salvaged Tapley’s life is David Liu, the Dudley Cabot Professor of the Natural Sciences and vice chair of the faculty at the Broad Institute of MIT and Harvard. 

“It’s exceedingly thrilling and also comes with a significant sense of obligation to ensure that — to the best of our ability — we have taken every measure to make these agents as safe and effective as can be for patient usage,” Liu remarked. 

Hundreds of millions of individuals globally are afflicted by genetic disorders. To assist them, Liu, with backing from the NIH, DARPA, and other federal entities, has expanded upon and explored alternatives to CRISPR-Cas9, the revolutionary gene-editing protein derived from bacteria that slices through DNA like scissors. 

“That technique of severing the DNA double helix is quite beneficial for gene disruption or removal,” he explained. “However, if your aim is to rectify a mutation that leads to a genetic disorder, using scissors is not the simplest method for achieving gene correction.” 

The limitations of the “scissors” method prompted Liu and his team, which included former postdocs Alexis Komor and Nicole Gaudelli, to devise two novel techniques for gene editing: base editing and prime editing. Base editing impacts the four nucleotide bases of a DNA strand — A, C, G, and T — instead of the entire double helix.

“You can transform a C into a T, a T into a C, an A into a G, or a G into an A,” Liu stated. “And those happen to be four of the most prevalent types of mutations that give rise to genetic disorders.” 

But what about genetic conditions induced by other forms of single-letter exchanges, or by excess letters, or by absent DNA letters? For those instances, Liu’s team, with the assistance of former postdoc Andrew Anzalone, conceived prime editors. Liu compared this tool to a word processor, capable of locating a defective segment of DNA and replacing it with a synthesized DNA segment dictated by the user. 

“There was no understanding of what CRISPR did, or whether it would be advantageous. But it intrigued enough curious minds to warrant investigation.” 

As of now, there are no fewer than 18 clinical trials utilizing base editing or prime editing to tackle a variety of diseases, with numerous patients already treated, Liu stated.

Liu associates his research with fundamental science — inquiries that aim to uncover new insights about the world without a definitive purpose in mind — that commenced at Japan’s Osaka University in 1987. There, a group of researchers observed something peculiar in DNA derived from E. coli bacteria: highly repetitive DNA sequences interspersed with non-repetitive ones, maintaining the same spacing. This phenomenon became recognized as Clustered Regularly Interspaced Short Palindromic Repeats, or CRISPR.

“There was no comprehension of what CRISPR was capable of, or whether it was going to be useful,” Liu stated. “But it was sufficiently intriguing for inquisitive individuals to explore. This is the cornerstone of fundamental science.” 

Over decades, scholars discovered that CRISPR represents a kind of immune defense that bacteria utilize to shield themselves from viruses. When a virus infiltrates a bacterial cell, the bacterium integrates a segment of the virus’s DNA as a form of genetic memory, enabling it to recognize and annihilate the virus should it come across it again. 

“You can envision a skeptic questioning, ‘Why should I be concerned about a bacterium’s capacity to destroy a virus?’” Liu remarked. “The response is that it ultimately led to all the CRISPR nuclease clinical trials, which consequently resulted in base editing and prime editing, allowing us to implement nearly any alteration in the DNA of living organisms, inclusive of rectifying the vast majority of mutations resulting in genetic disorders. All of this emerged from the fundamental science performed by geneticists who first examined these clustered regularly interspaced short palindromic repeats and pondered their function.” 

Liu is hesitant to label his technologies as a cure: “Scientists are generally wary of employing that term until there’s proof of extended periods without any obvious disease symptoms,” he explained. However, he added, “The evidence is already apparent: In several of these clinical trials, patients have ceased all medication and exhibit no symptoms of the ailment.”

Looking toward the horizon of research and innovation, Liu expresses deep concern regarding the current threat to collaboration between higher education and the federal government, particularly concerning emerging scientists.

“There exists a substantial amount of fear and turmoil presently hindering young scientists from entering the stage of their careers where they can make direct contributions to society,” he stated. “And that represents a significant tragedy.”

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