Many of the scientific breakthroughs that shape our lives begin with a question whose practical value is difficult to predict. How does a cell read its genetic instructions? How can a DNA molecule several meters long fit into a tiny nucleus and remain accessible for gene expression? These questions occupied my colleagues and me for decades. They seemed worth answering because they touched on the fundamental workings of life. Only as our understanding deepened did the connections to medicine and human health come into focus.
My path to molecular biology began through chemistry. In 1969, soon after graduating in Sweden, I joined Aaron Klug's (1982 Nobel Prize in Chemistry) group at the Medical Research Council Laboratory of Molecular Biology (LMB) in Cambridge. My first project was on transfer RNA, or tRNA. These small molecules help translate the information carried by messenger RNA into proteins. Knowing their chemical composition was essential, but to really understand how they performed that task, we needed to discover their three-dimensional structure.
For a long time, this meant painstaking experimental work. We purified RNA, tried to grow suitable crystals and searched for ways to interpret the X-ray diffraction patterns they produced. Progress depended on many people with different skills. I still remember the excitement of seeing an electron-density map in which the folded molecule became recognizable. The experience changed my understanding of biology. A molecule's shape could explain how it worked. That connection between structure and function has guided my research ever since.
Later, our work on the nucleosome addressed another fundamental problem: how does a DNA moleculeseveral meters long pack into chromosomes? The DNA in a human cell is organized by proteins, with sections of DNA wrapped around groups of histone proteins to form nucleosomes. A useful first picture is of a thread wound around a spool. But this packaging must also allow the cell to copy DNA and read the genes it needs. By understanding the nucleosome’s structure, we could start to ask how the cell controls access to its genetic code. In 2023, I had the honor to share the World Laureates Association (WLA) Prize in Life Science or Medicine with Karolin Luker and Timothy Richmond for the elucidation of the structure of the nucleosome.
This basic research is relevant to everyday life because the functioning of our bodies depend on cells using genetic information correctly. Understanding what goes wrong in disease requires us to understand what happens when things work normally. Research on chromosome organization and on the proteins that recognize DNA has helped build that foundation. In our own research on ATRX, a protein associated with chromatin, structural studies helped us see how certain mutations could be linked to inherited disorders. What seemed like an abstract molecular question turned out to have a direct connection to human biology and disease.
It is tempting, looking backwards, to describe scientific progress as a straight route from an idea to an application. My experience has been much less orderly. While studying a protein involved in controlling genes in yeast, we became interested in how it bound the ends of chromosomes, called telomeres. Those experiments led us to unusual DNA structures known as G-quadruplexes. These are four-stranded shapes formed by guanine-rich DNA sequences, adding another layer to the classic double-helix view of DNA. Our early results met considerable skepticism. Demonstrating that a structure could form in a test tube did not establish that it played a role inside a cell. It took years of experiments and collaboration, including work with Hans Lipps, to gather evidence that these structures form and are regulated in living cells. The process taught me to take unexpected observations seriously while being precise about what the experimental evidence shows, and what it doesn’t.
That distinction is important when scientists speak to the public. Understanding a mechanism associated with cancer does not mean we can immediately produce a treatment. A promising idea must pass through many more stages of investigation. We should explain why a discovery matters without overpromising. People deserve to know both what has been learned and what remains uncertain. The lengthy timescale of research is easier to appreciate when each step is made clear.
When explaining complex work, I begin with a question people can visualize. How does all that DNA fit into a cell? How does a cell find the instructions it needs? Images and simple comparisons can help, provided we explain their limits. The spool is a useful image for a nucleosome, but the DNA and proteins are dynamic, and the cell continually regulates their interactions. A good explanation should give the listener something real to imagine and a reason to keep asking questions.
Scientists can also describe how they reached their conclusion. Sometimes, an unsuccessful experiment, a puzzling observation, or a conversation with a colleague can be more revealing than a list of discoveries. At the LMB, people shared ideas and materials across groups. When I needed help with RNA sequencing, expertise was available down the hallway. That openness allowed us to connect methods that would otherwise have remained separate. It’s a part of science that should be more widely appreciated.
Science can help society make better decisions by improving the quality of the evidence available. It tests whether explanations fit the facts and whether an intervention really does what it’s supposed to. Decisions also depend on people's values and circumstances; scientific findings do not remove those choices. Scientists have a responsibility to distinguish observations from interpretations, make limitations clear, and correct their account when better evidence becomes available. These habits are useful well beyond the laboratory.
For science to continue benefiting society, young researchers need opportunities to pursue difficult questions whose answers cannot be guaranteed in advance. At the LMB, sustained support and open exchange gave us time to work through problems that took years. I hope future generations get that same opportunity. Looking back over my career, I could not have predicted where many of our experiments would lead. What I could recognize was the importance of asking questions, working carefully, and the excitement of understanding something a little better.
Daniela Rhodes is a structural biologist whose work focuses on chromosome structure and function. She shared the 2023 WLA Prize in Life Science or Medicine with Karolin Luger and Timothy J. Richmond for elucidating the nucleosome structure at atomic resolution.
The article reflects the author's opinions, and not necessarily the views of China Focus.
