When Daniel Branton, MCB’s Higgins Professor of Biology, Emeritus, began his scientific career in the 1950s, the cell membrane was one of biology’s greatest enigmas. Scientists argued bitterly about how these delicate barriers that define life were built – were they a layer of proteins associated with each other with a coating of lipids or were they sheets of lipids with proteins embedded within? “There were basically two camps,” Branton recalled. “Biochemists and more structurally oriented biologists arguing about the basic structure of membranes.”
Branton’s pioneering work helped resolve that decades-long debate. Through equal parts ingenuity, persistence, and playfulness, he provided direct biophysical evidence that biological membranes are bilayers of lipids – two sheets of lipid molecules bound together by the strange physics of water’s aversion to oil. In doing so, he helped define the molecular structure of the boundaries that surround compartments within each cell and that separate every living cell from its environment. That understanding, and the technologies he helped develop, became cornerstones of modern cell biology. But Branton’s legacy extends beyond the lipid bilayer. Over a career that spanned more than half a century, he contributed to three major aspects of biology: membrane structure, cell shape, and DNA sequencing. Each phase of his work built on the one before it, guided by an experimental curiosity that often led him to upend assumptions – and invent tools – along the way.
A Lucky Start
“I think throughout my life, what’s surprising is that I’ve had just extraordinary good luck,” Branton once said. Born in Belgium to American parents, he narrowly escaped the Nazi invasion during World War II. “I was just very, very fortunate,” he reflected. “I was born to Jewish citizens of the United States so that I could easily migrate to the United States.” That wasn’t possible for some members of his family who were exterminated in Nazi concentration camps.
He arrived in America as a child and initially pursued mathematics and physics as an undergraduate at Cornell. But his curiosity soon drifted toward the living world. “After the war,” he said, “I spent two summers working on a farm in France. It was right after the occupation, when food was still rationed in France. But as a teenager helping to generate food on a farm, life as a farmer seemed wonderful.” Those experiences nudged him toward plant physiology – a field that married his early love of physics with the rhythms of biology.
Branton earned his PhD in plant physiology at the University of California, Berkeley and joined the faculty. There, he began to ask questions that would transform biology.
Splitting the Cell Membrane
In the 1960s, the molecular composition of cell membranes was the subject of fierce debate. Biochemists had shown that membranes contained both lipids and proteins, but no one could agree on how they were arranged. Branton entered the fray with a new experimental approach: freeze-etching followed by electron microscopy that allowed him to see membranes as no one had before.
Traditional electron microscopy required chemically “fixing” and embedding cells in resin before slicing them into ultrathin sections. The process often distorted or destroyed delicate structures. Freeze-etching took a radical new approach. “What one does,” Branton explained, “is to freeze the material so rapidly that ice crystals that would perturb molecular arrangements inside a cell do not form.” Instead, the cells are vitrified into a solid glass-like mass that can subsequently be cracked open like hammering a chisel through a piece of glass.”
That method, developed by others during Branton’s time as a postdoctoral fellow in Switzerland, enabled him to visualize the interior of biological membranes in their native state. What he saw was astonishing. “The amazing thing,” he said, “was that the membrane itself cracks down the middle – between the two layers of lipid that are hydrophobically associated.” The split revealed the hidden internal faces of the lipid bilayer that constitutes the membrane continuum.
It was the proof biologists had been waiting for. “At the time that I got into this, there was a great deal of turmoil in the field,” Branton said. “One major figure even maintained that membranes were just an assembly of protein particles with some associated lipids. Freeze-etching was a major step forward – it demonstrated that frozen cell membranes behaved exactly as he showed do lipid bilayers frozen in a block of ice.
Still, convincing his peers wasn’t easy. “I realized I wasn’t going to have a job if I couldn’t really do a proof that convinced people that it is a bilayer,” he said with a laugh. “Fortunately, I was in a department that had a great deal of faith in me.” That faith – and Branton’s own creativity – paid off.
In a critical experiment, he and a postdoctoral student from a neighboring laboratory constructed model lipid bilayer membranes and froze them between an ice surface and a glass slide. He showed that when the ice was cracked off the glass slide, the lipid bilayers were cleanly split, as he had maintained that cell membranes were when frozen cells were cracked during freeze-etching. The experiment was featured on the cover of Science magazine. He and David Deamer (the postdoctoral student working in a neighbouring laboratory) made the equipment themselves – using parts from a toy hydraulic jack Branton found in a children’s store. “It was really a toy intended for kids to play with,” he recalled. “But the experiment turned out to be amazing. It succeeded on the first try.”
The publication not only silenced skeptics – it secured Branton’s promotion to associate professor. “It made the difference between my getting promoted or not,” he said. “It was the beginning of my real career.”
Coming to Harvard
By the early 1970s, Branton had become a rising star. Yet at Berkeley, he found himself caught in departmental turmoil as the university’s separate botany and zoology programs debated whether to merge into a unified biology department. “That was one of the major reasons I decided to accept the job at Harvard, where there was already a general department aware that life itself is the way to approach both plant and animal cells,” he recalls.
He joined Harvard in 1973, entering the era that would define his most influential work on cell architecture. “By the time I moved to Harvard,” he said, “I became very interested in the organization of red cell membranes as an example of membranes – how these membranes interacted with the other structures inside the cell.”
Red blood cells, with their distinctive biconcave shape, became his model system.
Using his freeze-fracture technology, Branton and his students explored how proteins and cytoskeletal filaments interacted with the cell membrane to give the red cell its remarkable flexibility and biconcave shape. Their Science review of evidence from several laboratories, including their own, provided some of the first detailed explanations of cell shape— concepts that would inform decades of work on cytoskeletal dynamics and membrane mechanics. Branton often credited his students for those insights. “It was a lengthy feud,” he said wryly, referring to the spirited debates that followed. “But my students played an important role in developing the understanding of how a network of proteins underlying biological membranes could give rise to cell shape.”
Lifelong Friendships and Freeze Frames
Science, for Branton, was as much about human connections as it was about discovery. One of his longest collaborations had begun by chance in a laboratory neighboring his own. “I walked into a neighbouring faculty’s lab one day to ask the faculty member in charge whether he knew anyone who had had experience building lipid bilayers on glass,” he remembered. “The faculty wasn’t around, but one of the postdocs, Dave Deamer, raised his hand.” The two struck up an impromptu collaboration that produced the landmark Science bilayer experiment – and a friendship that would last a lifetime. “It’s just been a very good example of lifelong friendships as a result of doing science,” Branton said.
Decades later, that same friendship would lead to his third important contribution: reading the sequence of nucleotides in DNA by pulling a strand of DNA through a tiny passageway – nanopore sequencing.
Nanopores and DNA sequencing
As Branton approached retirement age toward the end of the 1980 biologists worldwide were seeking new, less expensive methods of significantly increasing the speed and accuracy of reading the sequence of nucleobases in DNA. Chatting with Deamer, Branton discovered that both of them had parallel ideas about sequencing DNA by pulling strands of DNA through some kind of an interface. But Branton thought that Deamer’s idea of using a very small diameter channel or nanopore through the interface created by a membrane was far better than any of his own ideas. Branton was therefore delighted when Deamer generously invited him to collaborate in developing what eventually came to be known as “nanopore sequencing”.
The idea underlying nanopore sequencing was elegant and simple – but technically daunting. Together, both Deamer’s group, including Mark Akeson, Professor of Biomolecular Engineering at UC Santa Cruz, and Branton’s group, including Gene Golovchenko, Professor of Physics at Harvard University, solved many of the biological and biophysical problems that made it possible for nanopore sequencing to become the foundation for what is now one of the fastest-growing commercial sequencing technologies in genomics.
It was, in many ways, the culmination of his life’s work. The same principles of hydrophobic bonding, membrane structure, and molecular precision that guided his early discoveries were now being harnessed to read the code of life itself.
A Career of Firsts
From freeze-etch electron microscopy to nanopore sequencing, Branton’s career embodied the spirit of experimental courage. He had a knack for asking the simplest – and most profound – questions: What holds a membrane together? How does a cell keep its shape? What if you could pull DNA through a hole and read it as it goes through the hole?
He often approached science with a sense of play. “Most people think of experiments as these monumental undertakings,” he said, “but sometimes, the simplest setup – something you buy at a toy store – can change everything.”
Branton’s humility and humor made him a beloved mentor at Harvard. He was quick to deflect credit to his students, colleagues, and department, which he once described as “a place where people have faith in each other’s ideas, even when their ideas are brand new.”
In his later years, Branton looked back on his career with quiet pride and characteristic modesty. “Throughout my life, I’ve had extraordinary luck,” he said. “Good mentors, good students, and good timing. Science has given me lifelong friendships and the satisfaction of knowing that what we learned will keep unfolding long after I’m gone.”
His discoveries did more than illuminate the architecture of life – they reshaped how scientists see the cell itself. The methods he pioneered still underpin modern structural biology, and the nanopore technologies he helped to develop continue to revolutionize genetic sequencing.
Looking back, perhaps his greatest gift to science was his example: an experimentalist unafraid to improvise, to question orthodoxy, and to find wonder in the details of molecules and membranes. “The amazing thing about science,” he said, “is that even when you think you’ve seen everything, the next experiment can split the world right down the middle – and show you something entirely new.”
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