Hagan Bayley: Making DNA “Slow Down”
Following 25 Years of Human Genome International Symposium held by Changping Laboratory, nanopore technology pioneer Hagan Bayley sat down for an interview. From being introduced to science by good teachers when he was a young student, to helping found Oxford Nanopore Technologies, and eventually reducing a sequencing instrument to a size smaller than a mobile phone, Bayley spoke less about any particular product than about fundamental science, patience, and an idea that took years to fully work out.
He has always believed that technologies capable of truly transforming reality must first address the underlying problems in chemistry, physics, and biology. Products can be designed, but without solid fundamental research, it is difficult to create something genuinely different. In his view, the story of nanopore sequencing is a perfect example.
Seven Years to Make the Concept Work
In the interview, Bayley recalled that the company was fortunate in its early days. Although the initial round of financing was limited, the investors were willing to wait patiently and give the team the freedom to pursue high-risk research and development. The second and third rounds of financing followed successfully. It was precisely this patience and tolerance for uncertainty that allowed the concept of nanopore sequencing to mature—yet it still took approximately seven years to become technically viable.
This was by no means an endeavor that could be accomplished by an individual or through a single technology. Bayley recalled that chemists, physicists, biologists, device engineers, and signal-processing specialists had to integrate their respective advances and work together to solve the challenges. A single nanopore could demonstrate the principle, but it could not support large-scale sequencing. The team therefore had to expand the nanopore array from roughly 500 pores initially to several thousand pores before sequencing throughput could reach a practically useful level. Looking back on the entire development process, Bayley is more inclined to view it as a story of technology, capital, and talent working together patiently until the results finally emerged.
First, Make DNA “Slow Down”
One of the earliest obstacles in nanopore sequencing sounds deceptively simple: DNA was moving too fast to be captured and measured. Bayley compared the challenge to threading a needle. The pore had to be sufficiently precise for DNA to enter it; even after entering the pore, however, individual bases passed through at microsecond timescales, leaving the instrument insufficient time to resolve their signals one by one.
The team came up with an ingenious solution: using an enzyme as a molecular ratchet to move DNA one base at a time, slowing the signal down by more than three orders of magnitude. At the time, nanopores had only been used to identify small molecules, and no one knew whether long DNA molecules could be sequenced stably. Only when all four DNA bases could finally be distinguished clearly did the team become confident that the approach was feasible.
Nanopores Can Read More Than DNA
Looking toward the future, Bayley appears reluctant to place strict boundaries on what nanopore technology can achieve. Nanopores can read DNA and RNA and may potentially detect RNA modifications. Proteins, polysaccharides, and small molecules may also produce signals that can be captured by nanopores. Of course, different molecules require different nanopore architectures and analytical approaches, and many challenges remain to be resolved in the laboratory.
Conclusion
During the interview, Bayley encouraged young people to engage with science as early as possible: the earlier one discovers the intrinsic fascination of science, the more likely one is to be willing to pursue it as a long-term endeavor. Today, MinION sequencers have become smaller than a mobile phone and have begun to enter the educational sphere through science courses. A task that once required a large-scale sequencing center can now potentially become a hands-on gateway for young people to engage with genomics.
Peter Campbell: The Human Body Is a Book That Is Constantly Being Rewritten
Cancer genomics expert and Fellow of the Academy of Medical Sciences (UK) Peter Campbell took the research question one step deeper in the interview—from “What mutations does a tumor carry?” to a broader question: How do an individual’s cells accumulate genetic changes throughout life, how do these changes give rise to clones within tissues, and under what circumstances do they become associated with disease? Campbell previously led research on cancer, aging, and somatic mutations at the Wellcome Sanger Institute and was a co-leader of the Pan-Cancer Analysis of Whole Genomes (PCAWG) project.
The Human Body Is a Book That Is Constantly Being Rewritten
Somatic mutations are genetic changes acquired after birth. Cell division, DNA damage, and DNA repair all influence the generation of mutations. Over time, different cells within the same tissue may acquire distinct combinations of mutations, giving rise to clones that are similar but not identical. Campbell likens the human body to a book that is continuously being revised. We are born with a germline genome, but beginning in embryonic development, successive cell lineages continuously acquire new genetic changes. These changes do not occur exclusively in cancer cells—normal tissues can also harbor clones carrying driver mutations. Some may expand, while others are constrained by the tissue environment. He emphasizes that this form of “evolution within an organ” is not simply a scaled-down version of species evolution. Rather, it represents a long-term process of selection occurring within an individual. Certain mutations may give cells a proliferative advantage, allow them to evade immune clearance, or confer an advantage under chronic tissue injury. However, the presence of a mutation does not, in itself, mean that cancer has been detected.
Uniqueness and Convergence Coexist
After analyzing more than 2,600 cancer genomes across 38 tumor types, PCAWG found that cancer exhibits both uniqueness and convergence. The combination of mutations in each patient’s tumor is unique and is almost never reproduced in its entirety in another patient. At the same time, similar driver-gene alterations and mutational processes repeatedly emerge across different tumor types. The former highlights the complexity of personalized treatment, whereas the latter suggests that cancer evolution is not without regularity or predictable patterns. For precision medicine, the challenge lies in determining, within the unique tumor of an individual patient, which alterations contribute to clonal expansion, which are merely passenger events, and which recurrent principles of tumor evolution might be amenable to pharmacological intervention. Addressing these questions requires integrating genomic sequencing with functional experiments, spatial information, treatment responses, and longitudinal follow-up. Even when a gene is recurrently mutated across multiple tumor types, mutation frequency alone cannot establish that the gene plays the same functional role in every cancer.
Beyond Cancer
Somatic mutations and clonal selection are part of normal aging, but whether they also contribute to cardiovascular disease, immune disorders, or other age-related diseases remains incompletely understood. Different tissues have different rates of mutation and different selective environments, and clonal expansion in healthy tissue does not necessarily progress toward malignancy. Future research will need to track changes within individuals’ tissues over time and use experimental approaches to determine the actual functional consequences of specific mutations. Only by placing cellular lineage, tissue environment, and clinical outcomes within a single chain of evidence can research on somatic evolution ultimately be translated into risk assessment or therapeutic strategies.