Mary Lyon discovered X-inactivation - the process that enables female mammals to avoid genetic overdose by randomly switching off one X chromosome in each of their cells - some 40 years ago. In the past 20 years, she has received six awards in recognition of this discovery, including the recently announced Wolf Prize in medicine, worth US$100,000. At 71, Lyon will use the award to continue her work at the Medical Research Council's Mammalian Genetics Unit at Harwell, south of Oxford in England.

Her colleagues say she is quiet, unassuming, yet utterly determined. For years she ruled the genetics division at Harwell with a "very firm hand". Her conversation is often punctuated by "great long periods of silence," but there is no need to panic; she is thinking. "Mary is really an exceptional scientist - incredibly disciplined and able to see right through a problem," says Bruce Cattanach, director of the Mammalian Genetics Unit, formerly known as the Radiobiology Unit.

The problem puzzling Lyon 40 years ago centred round a ragbag of 'mosaic' anomalies that cropped up only in female mammals. The radiation experiments that were her 'bread-and-butter' had produced strains of mice in which only the females had oddly spotted fur. Lyon paid attention to these mice, not least because she "really likes mice," says Cattanach. "She goes in to talk to them, she is very sweet with the animals." With the help of the mice, she published the solution to the puzzle in Nature on 22 April 1961. At the time, J.B.S. Haldane said: "I wish I had thought of it."

Scientists in North America were quick to appreciate the beauty of Lyon's idea and to see its relevance to sex-linked genetic diseases in humans. "Geneticists hail new hypothesis," trumpeted the New York Times, when Lyon visited Manhattan in 1963 to attend a conference on congenital malformations. The "unexpected heroine" of the meeting, said Time magazine, was "a quiet Englishwoman who presented no paper and who is, of all things, editor of the semi-annual Mouse News Letter". For years, X-inactivation was called 'Lyonization', though Lyon herself disapproved of the tag.

Back at home, however, Lyon was slower to gain the plaudits she deserved. A leading mouse geneticist of the day, Professor Hans Gruneberg, launched a "savage" campaign to discredit her, but "Mary was tough - she kept coming back," says Cattanach, and eventually Gruneberg conceded defeat. Yet his influence may have delayed Lyon's election to the Royal Society - she was at last made a Fellow in 1973.

It was a "very difficult and very depressing" time for Lyon, who had first come into contact with Gruneberg in 1950 when he examined her PhD thesis. Eleven years on, "he may not have realised I wasn't a PhD student any more - that I didn't have to ask him for permission," speculates Lyon. Misogyny may also have played its part.

Peer review could have been her downfall, but in those days, Nature did not invariably send papers out to referees. "It is interesting to speculate whether I would ever have managed to get it published if they had," muses Lyon. Gruneberg would have been the obvious person to review the paper.

As it was, Lyon had to fight her corner even to be allowed to do the research that led up to the discovery of X-inactivation. The MRC's Radiobiology Unit was set up in the aftermath of Hiroshima, to study the genetic effects of radiation. "We were under a lot of pressure to concentrate almost entirely on standard radiation work," Lyon remembers. Yet she knew that the mutants thrown up by the irradiation experiments could also provide valuable insights into fundamental genetics, at a time when mouse genetics was poorly understood. "The MRC is so proud of this work now, but she battled for it," says Cattanach.

But fighting battles was nothing new to Lyon. At school during the war years, she struggled to be allowed to do science A-level examinations, only to gain a place at Cambridge University in the days when that august institution did not officially award degrees to women. Intrigued by C.H. Waddington's writings about genes and development, she embarked in 1946 on a challenging PhD in mouse genetics, about which almost nothing was known at the time. Early in her third year, however, the genetics professor, R.A. Fisher, "withdrew the facilities I was using - a primitive lab - to turn it over to bacterial genetics". She found shelter in Waddington's "stimulating and supportive" group in Edinburgh, and stayed on to begin work on the genetic effects of radiation, funded by the MRC. In 1955, she moved with the group when it was transferred to larger facilities at Harwell, where she found secure funding but more pressure to concentrate on radiation hazards.

If pressures for routine radiological research once threatened to displace innovative genetic investigations, today it is an overweening emphasis on molecular work that distorts the research agenda. "People who understand how to do classical genetics with mice are very thin on the ground," says Lyon. Even worse, the future of mutant mouse lines throughout the world is far from secure. "Grant-givers tend not to want to pay money to keep genetic stocks going, even though so much is coming out of mouse genetics," Lyon says. "But if only we can keep the battle going, the pendulum may swing back as people recognize the importance of keeping all this going." Let us hope she wins this battle too.

Physical Map of the Mouse X Chromosome - from the Mammalian Genetics Unit, this preliminary summary of their mapping work includes 484 markers. The MGU also has a page on Imprinting, which provides references (often linked to PubMed citations) to their work on imprinted genes of the mouse.

The Human Genome Organisation: History, Purposes and Membership - article by Victor McKusick describing the early history of HUGO, of which Mary Lyon was a founding member.

The Jackson Laboratory - maintains inbred and mutant strains of mice and provides genomic information. The MGU also maintains an Embryo Banking Service for the preservation of unique genetic stocks.

The Lyon Hypothesis - discusses the experimental evidence that led to Mary Lyon's hypothesis of X chromosome inactivation. From a lecture on Sex Differentiation and Sex Chromosome Abnormalities at NYU Medical School.

Inactivation Specific Transcript - OMIM entry that discusses the molecular mechanism of X chromosome inactivation.

Physical Map of the Mouse X Chromosome - from the Mammalian Genetics Unit, this preliminary summary of their mapping work includes 484 markers.