For the past nine years, the March of Dimes Foundation has been awarding a prestigious research prize in developmental biology. This May, the prize goes to Professor Mary Lyon, a distinguished mouse geneticist who is best known for her contributions to our understanding of X inactivation, originally named 'Lyonization' in her honour. Through hard work and remarkable insight, Mary demonstrated the existence of X inactivation and showed that this process occurred early in embryonic development. However, this was really only the beginning of her contribution to the mouse-genetics community. She also led meticulous research that allowed the mouse t complex to be unravelled during the 1980s. As the Chair of the mouse-gene nomenclature committee during the 1970s and editor of the mouse genetics 'bible', 'Genetic Variants and Strains of the Laboratory Mouse', she confirmed her place as one of the most important figures in the field over the past 50 years.

What achievements in your career are you most proud of?

Well, X inactivation was the most important thing for me. I also had the opportunity to build the mouse-genetics alliance here into a major mouse genetics lab in the world, which I was also pretty proud of. Of course, there is my work on the t complex but that is rather esoteric. At one time, the t complex was thought to be something important in mouse development, but now it's more of a curiosity, so I'm less proud of that than I am of the X-chromosome inactivation work.

What have been your major disappointments?

I would like to have been able to do more work on X-chromosome inactivation. I discovered it but I wasn't really given much opportunity to actually work on it. It was a bit frustrating seeing people in universities doing work on it when I couldn't work on it myself. The Medical Research Council regarded it [my lab] as a radiation laboratory not for doing formal genetics, and so I was unable to do much work on X inactivation. I also would have liked to have been able to develop the formal genetics side of this lab more than I could. I always told the MRC that they needed to support formal genetics to help the understanding of radiation genetics.

Thomas H. Huxley said, “The great tragedy of science — the slaying of a beautiful hypothesis by an ugly fact”. Is this something that you have experienced yourself?

Well yes, I experienced it lots of times. I think one tends to forget the ideas that don't work out. As far as the t complex being a curio, I certainly had disappointments, ideas about that that didn't work out, as well as ideas that did work out of course. I think everybody has tremendous ideas that don't work out. I seem to remember that Peter Medawar once said that 90% of a scientist's work was a waste of time. If he thought that 90% of his work was a waste of time, then other people must have something like 95 or 99% of their work being a waste of time! What's he [a scientist] doing all the time? Setting up hypotheses and then trying to demolish them. Too often, he just succeeds in demolishing them and the ideas are consigned to the dustbin.

What was it like to work with R. A. Fisher?

It was a rather mixed experience — he was very irascible. He would fly into tempers and he was difficult to work for, largely because of the irascibility, but on the other hand, his theoretical ideas were excellent, and I think it gave me a good start in scientific thinking to work with him. He had a mouse colony ... [and] that was where I first started doing mouse genetics. I don't think he made any really major contributions to mouse genetics. I think it was his theoretical work that he is known for and that was his major contribution.

Would you like to have started your career now, with a fully sequenced mouse genome, or when you did, at a time when we knew much less?

I think it's a very exciting time for mouse geneticists now. There is so much waiting to be found out about the interaction of genes in development: the potential is there [to do that] now that they have finished it [the mouse genome]. On the other hand, I think I was very privileged to start out when I did because I've had the opportunity to see all the enormous advances that there have been during the time that I have been working. When I started, I think there were about 100 mutant genes known and, as far as the map of the genome went, I think there were 10 linkage groups with 2 or 3 genes in each group, and now you've got the sequence of the 30,000 genes. To have seen that all develop was a privilege that I can't quite imagine people having who are setting out today.

Over your long career, what do you see as the most important breakthroughs that have been made, in genetics in general, and in mouse genetics in particular?

Well, obviously for everybody, it has been the recombinant DNA work, PCR and sequencing. Also, I think in mouse genetics and mammalian genetics, it has been the embryo surgery [embryonic stem (ES) cell manipulation] that has been so valuable. It has made it possible to do all the knockouts and transgenic work that people can do nowadays, which is very valuable in finding out the functions of genes.

So, do you think that the mouse will retain its prominence as a genetic model in the future?

Yes, I think it will remain the main mammalian model that there will be in the next 50 years. Of course, they are able to do embryo surgery [ES cell manipulation] in other species now, such as Dolly the sheep. There are other species that I am sure will provide valuable insights into some things, but I think the mouse will be the main model because of the ability to keep so many mice and do such elaborate embryo surgery [ES cell manipulations] on them, I think it will keep them the most important mammalian model.