Eureka Moments

Centenary News

Tim Hunt in conversation with Hugh Pelham Eureka Moments: the protein that disappeared Downloaded from http://portlandpress.com/biochemist/article-pdf/33/3/42/6836/bio033030042.pdf by guest on 30 September 2021

Amy Cox (Communications Manager)

As part of our Centenary celebrations, a number of the Society’s Honorary Members have been asked to talk about the important moments in their careers and the future of the discipline. These interviews will be made available throughout the year on the Society’s website as a series of pod- casts. The third to be released is that of Tim Hunt who spoke to Hugh Pelham about discovering the protein that disappeared.

When organisms grow, their cells undergo a remark- ably complex cycle of division. Tim Hunt discovered the molecule that controls this process. Even though his research has achieved the highest accolades in science, Tim maintains that even the best science requires luck as well as lateral thinking. Hugh Pelham studied for his PhD in Tim’s labo- ratory at Cambridge University and remembers the Professor of Biochemistry remarking that he was “very brave” to be going to work with Tim as a gradu- ate student. For Tim had a reputation for doing things that were more difficult than those that other people were doing. Hugh remembered complaining to Tim about an experiment that hadn’t worked only for Tim Hugh Pelham and Lilley Mitchell to say, “always remember, if at first you don’t succeed, give up and try something else”, a mantra that Hugh took to heart. Hugh explained, “it means don’t just keep doing the same thing that’s failing, think of an- other way around your problem, come at it from a different angle.” Tim wanted to understand the way protein pro- duction inside a cell is controlled and, when eggs are fertilized, how they start making proteins. Sea urchins were often used as a model organism for studying fertilization. So when the opportunity came in 1966 for Tim to work on sea urchins in the Woods Hole Marine Biological Lab in Massachusetts, he jumped at the chance and it was there that he uncovered a surprising result. Tim’s chance discovery revolutionized our under- standing about the way in which the cell cycle works. Filming Tim Hunt (left) and Hugh Pelham (right)

Tim Hunt and Hugh Pelham in conversation

His experiment revealed a pattern of protein synthesis in sea urchin eggs over time. He was astonished to see that one particular kind of protein seemed to disap- pear in a process known as proteolysis and then reappear at regular intervals. Tim explained “Nobody had even thought proteolysis might be important for cycle progression; it wasn’t even a remote theoretical possibility. There are a lot of theoretical possibilities that get discounted either because they seem not possible or because they are not thought very likely. But it turns out that’s not a very good argument.” Two other biologists, Paul Nurse and Lee Hartwell, who went on to win the Nobel Prize along with Tim, had been working on the genetics of cell division in yeast. They had identified many genes that are required for this process, in particular cyclin-dependent kinase (CDK), which, when inactive, causes the cell cycle to stop. That is the engine of the cell cycle, it’s a protein kinase that goes around and modifies a whole series of proteins in the cell which trigger all of these complex events in the cell cycle. Hugh used the idea of a bus route to explain, “It’s a bit like having a bus going on a circular route, if you kill the engine, the bus doesn’t go anywhere, but what’s missing from that is the driver who accelerates, steers, stops and starts the whole thing. So the control of this kinase is done by these proteins called cyclins which activate the kinase and control its activity.” Tim and his colleagues now believed that cyclins were universally important, but more proof was needed to convince the sceptics. Over the next few years, it gradually became clear that this was not a special thing in marine organisms. With the convergence of work on frogs, sea urchins, yeast and eventually mammalian cells, there was a growing realization that this was important and universal. For Tim, all of these bizarre scattered observations fell into place and he realized that he had the key to explain all these bizarre things no one else had understood. Tim was extremely surprised when he got the call from Stockholm, “this was a discovery that I had made with my own hands and my own brain and my own eyes, nobody else was involved and many people had missed it.” Tim and Hugh both agree that the excitement of discovery is a significant moment for young scientists, “I always think it’s important for them to discover something – the fact that you know something that no one else knows is such a thrill.” ■

To hear more about Tim’s pioneering work, watch the interview in full at www.biochemistry.org/Centenary/EurekaMoments