Physicist Stephen Hawking has died at the age of 76, his family has said.

The Briton was known for his groundbreaking work with black holes and relativity, and was the author of several popular science books including A Brief History of Time.

His children, Lucy, Robert and Tim, said: "We are deeply saddened that our beloved father passed away today.

"He was a great scientist and an extraordinary man whose work and legacy will live on for many years."

Stephen Hawking - who died aged 76 - battled motor neurone disease to become one of the most respected and best-known scientists of his age.

A man of great humour, he became a popular ambassador for science and was always careful to ensure that the general public had ready access to his work.

His book A Brief History of Time became an unlikely best-seller although it is unclear how many people actually managed to get to the end of it.

He appeared in a number of popular TV shows and lent his synthesised voice to various recordings.

Stephen William Hawking was born in Oxford on 8 January 1942. His father, a research biologist, had moved with his mother from London to escape German bombing.

Hawking grew up in London and St Albans and, after gaining a first-class degree in physics from Oxford, went on to Cambridge for postgraduate research in cosmology.

As a teenager he had enjoyed horse-riding and rowing but while at Cambridge he was diagnosed with a form of motor neurone disease which was to leave him almost completely paralysed.

As he was preparing to marry his first wife, Jane, in 1964 his doctors gave him no more than two or three years of life.

But the disease progressed more slowly than expected. The couple had three children, and in 1988 - although Hawking was by now only able to speak with a voice synthesiser following a tracheotomy - he had completed A Brief History of Time - a layman's guide to cosmology.

It sold more than 10 million copies, although its author was aware that it was dubbed "the most popular book never read".

Celebrity

Hawking discovered the phenomenon which became known as Hawking radiation, where black holes leak energy and fade to nothing. He was renowned for his extraordinary capacity to visualise scientific solutions without calculation or experiment.

But it was perhaps his "theory of everything", suggesting that the universe evolves according to well-defined laws, that attracted most attention.

"This complete set of laws can give us the answers to questions like how did the universe begin," he said. "Where is it going and will it have an end? If so, how will it end? If we find the answers to these questions, we really shall know the mind of God."

Hawking's celebrity status was acknowledged even by The Simpsons - he was depicted drinking at a bar with Homer, suggesting he might steal Homer's idea that the universe is shaped like a doughnut.

He also appeared as himself in an episode of the BBC comedy series, Red Dwarf and as a hologram of his image in Star Trek: The Next Generation.

The rock group Pink Floyd used his distinctive synthesised voice for the introduction to Keep Talking, on their 1994 album The Division Bell.

Undeterred by his condition, he continued his work as Lucasian Professor of Mathematics at Cambridge University, and in 2001, his second book - Universe in a Nutshell - was published.

Erratic

He believed his illness brought some benefits; he said before he developed the disease he had been bored with life.

But his condition inevitably made him dependent on others. He often paid tribute to his wife, who had looked after him for more than 20 years, and friends and relatives were shocked when he left her for one of his nurses, whom he married in 1995.

By 2000, Hawking was a frequent visitor to the emergency department of Addenbrooke's Hospital in Cambridge, seeking treatment for a variety of injuries. Police questioned several people about allegations that he had been subjected to verbal and physical abuse over a period of years.

He was known to be an erratic, almost reckless driver of his electric wheelchair, and Hawking insisted his injuries were not caused by abuse. No action was taken.

In 2007, he became the first quadriplegic to experience weightlessness on board the so-called "vomit comet", a modified plane specially designed to simulate zero gravity. He said he did it to encourage interest in space travel.

"I believe that life on Earth is at an ever-increasing risk of being wiped out by a disaster such as sudden nuclear war, a genetically engineered virus, or other dangers. I think the human race has no future if it doesn't go into space. I therefore want to encourage public interest in space."

In 2014, the film The Theory of Everything was released, based on Jane Hawking's account of their courtship and marriage. Hawking himself met Eddie Redmayne as part of the actor's preparation for taking on the role of the scientist.

In a series for the Discovery Channel, he said it was perfectly rational to assume there was intelligent life elsewhere but warned that aliens might just raid earth of its resources and then move on.

He once wrote that he had motor neurone disease for practically all his adult life but said that it had not stopped him having an attractive family and being successful in his work.

"It shows," he said, "that one need not lose hope."

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In science, we don’t often get to talk about male repression, but a new discovery gives us just such a chance. It turns out that ovaries can only remain ovaries by constantly suppressing their ability to become male. Silence a single gene, and adult ovaries turn into testes. That adult tissues can be transformed in this way would be surprising enough, but doing so by changing a single gene is truly astonishing.

As embryos, our gonads aren’t specific to either gender. Their default course is a female one, but they can be diverted through the action of a gene called SRY that sits on the Y chromosome. SRY activates another gene called Sox9, which sets off a chain reaction of flicked genetic switches. The result is that premature gonads develop into testes. Without SRY or Sox9, you get ovaries instead.

But Henriette Uhlenhaut from the European Molecular Biology Laboratory has found that this story is woefully incomplete. Maleness isn’t just forced onto developing gonads by the actions of SRY – it’s permanently kept at bay by another gene called FOXL2.

Uhlenhaut developed a strain of genetically engineered mice, whose copies of FOXL2 could be deleted with the drug tamoxifen. When she did this, she found that the females’ ovaries turned into testes within just three weeks. The change was a thorough one; the altered organs were testes right down to the structure of their cells and their portfolio of active genes. They developed testosterone-secreting Leydig cells, which pumped out as much of the hormone as their counterparts in XY mice. They only fell short of actually producing sperm.

Uhlenhaut found that FOXL2 and SOX9 are mutually exclusive – when one is active, the other is silent and vice versa. The two genes are at opposite ends of a tug-of-war, with sex as the prize. FOXL2 sticks to a stretch of DNA called TESCO, which controls the activity of Sox9. By sticking to TESCO, FOXL2 keeps Sox9 turned off in the adult ovary. Without its repressive hand, Sox9 switches on and sets about its gender-bending antics.

FOXL2 also has a partner-in-repression – the oestrogen receptor, a docking molecule for the hormone oestrogen. The two proteins interact with one another and they cooperate to block Sox9.

The same genes may help to explain the frequent acts of gender-swapping among, fish, reptiles and birds (no, Steve Connor, “one of the great dogmas of biology” is not that “gender is fixed from birth”). In these animals, oestrogens often cause males to change sex into females, and falling levels of oestrogen can trigger the reverse transformation. FOXL2 may also be involved. 

The fact that oestrogen helps to maintain the gender of mice is surprising. Unlike other back-boned animals, mammals are thought to be largely insensitive to levels of sex hormones outside of development. However, Uhlenhaut suggests that oestrogen’s role in keeping ovaries and ovaries may explain why women sometimes appear slightly more masculine after the menopause, a time characterised by falling oestrogen levels.

There have been hints from many species that FOXL2 plays an important role in determining sex. People who inherit faulty copies of the gene can develop a rare disease called BPES that often leads to infertility because of failing ovaries. Goats whose FOXL2 isn’t controlled properly develop a condition called polled intersex syndrome (PIS), where they become males despite carrying two X chromosomes. Females that lack the gene altogether fail to develop proper ovaries at all.

Understanding how gender is set and maintained is vital, for it is such a basic and pervasive element of our lives. Uhlenhaut’s work isn’t just of academic interest. It could also help to treat disorders of sexual development. It could also change how gender reassignment therapies are done, paving the way for gene therapies rather than multiple painful surgeries.