Richard Losick, Maria Moors Cabot Professor of Biology, Emeritus in Harvard’s Department of Molecular and Cellular Biology, is about to publish what he describes as his “last paper”—though it is not a research article in the traditional sense. Instead, it appears in a new “Commentary” section of the Journal of Molecular Biology (PDF), created expressly for historical and interpretive reflections. The piece revisits one of the most celebrated papers in the history of molecular biology: the 1961 publication in Nature, “General Nature of the Genetic Code for Proteins,” by Francis Crick, Leslie Barnett, Sydney Brenner, and Richard J. Watts-Tobin, which proposed that the genetic code is composed of non-overlapping triplets.
That landmark paper has long been regarded as breathtaking in its simplicity and explanatory power. Using bacteriophage T4 mutants, Crick and colleagues reasoned that the genetic code must be read in units of three nucleotides—triplets—that specify amino acids. Their conclusions were later borne out in every detail, cementing the triplet code as one of the cornerstones of molecular biology.
But as Losick argues in his upcoming article, the evidence supporting that claim has often been oversimplified. He revisits the data in light of later DNA sequencing results and suggests that one of the pivotal experimental examples—still taught today—did not in itself provide unambiguous proof of the triplet code.
A Subtlety in the Code
In the 1961 paper, the authors relied on mutagens that introduced insertions and deletions, which they represented as “+” and “–” mutations. Combining three of the same type—for example, three insertions—restored the proper reading frame, yielding normal phage growth. This result was taken as evidence that codons must be read in groups of three.
However, as Losick notes, a key assumption in this analysis turned out to be mistaken. Nearly two decades later, in a 1987 paper, Larry Gold and colleagues sequenced several of the original mutants and discovered that one of the so-called “–” mutations was in fact a +2 insertion. When combined with two single-base deletions, the net effect was zero—not a shifted reading frame. In other words, the famous triple mutant that appeared to prove the triplet code could also be reconciled with alternative possibilities, such as a quadruplet code.
“The original authors were absolutely right—the code is triplet and non-overlapping,” Losick says. “But they were right for reasons different from the way most people tell the story. The conclusions were more of a house of cards than many realize.”
The paper highlights this nuance, demonstrating that the evidence lies not in the oft-cited “Table 3” of the 1961 paper, but in another set of double mutant experiments that truly required a triplet code to explain.
Teaching, Talking, and a Revelation
While the findings themselves are striking, Losick is equally clear that the story behind the paper is just as important. Far from being born in the lab, his “last publication” emerged through teaching, conversations with colleagues, and insights from students.
The spark came during a new MCB course on the history of molecular biology (MCB 149) that Losick began teaching several years ago. In discussing the Crick paper with students, he was challenged to revisit some of the mathematics—specifically, the modular arithmetic used by Crick and colleagues to describe insertions and deletions. Two students in the class, Adam Strandberg (now a Harvard graduate student) and Ari Hilibrand (then an undergraduate, now in medical school), mentored him through the math.
The conversation deepened when Sean Eddy, Professor of MCB and of Applied Mathematics, handed Losick the 1987 Gold paper and the two began discussing its implications nearly 35 years after its publication. “I woke up in the middle of the night,” Losick recalls, “realizing that if the so-called minus one mutation was actually a plus two, then the famous result was not evidence for a triplet code at all.”
Eddy became a frequent sounding board, supplying a figure for the article and offering extensive feedback. Another MCB colleague, Craig Hunter, also engaged Losick in spirited debate. “Sean and Craig both took the view that Crick and colleagues anticipated this subtlety in their original paper,” Losick explains. “My perspective was different—that they overstated the case. But those discussions sharpened my thinking enormously.”
Even the writing process was collaborative. Polina Dimitrova Kehayova, a colleague from MCB’s undergraduate education team and MCB Scientific Director, provided detailed editorial feedback. Strandberg and Hilibrand continued to help refine the arguments. The result, Losick emphasizes, is not just a paper but the product of a “whole community of people” coming together around a classic question.
Because the piece does not present new experiments but instead reevaluates old ones, Losick submitted it to the Journal of Molecular Biology as a historical perspective. Editors responded by creating a new category—“Commentary”—to house it. The reviewers, Losick says, were enthusiastic, seeing value in revisiting even the most foundational conclusions of the field.
The publication is also personally meaningful. “This really is my last paper,” Losick says. “I didn’t do any experiments—everything came out of teaching, reading, and conversations. It was fun, and unusual, and a way to say something about a breathtaking moment in the history of molecular biology.”
Though the genetic code has been understood for decades, Losick’s Commentary reminds us that science is not only about results, but also about interpretation, re-interpretation, and the conversations that move a field forward. As he puts it, “At the end of the day, Crick and colleagues were right. But how we tell the story matters, because it shapes how generations of students understand the history of their science.”
