Journeys of discovery: Azim Surani on the earliest stages of life

Failed experiments as a student didn’t deter him - Azim Surani has spent his entire career trying to understand early mammalian development.

This year marks the 40th anniversary of his discovery of genomic imprinting - the process in which specific genes are tagged, turning them on or off at the very earliest stage of life.

Surani has transformed scientific understanding of the different contributions of maternal and paternal genes to development in mammals, and how these genes are regulated.

The resulting field of epigenetics has now exploded - and his discovery holds wide-ranging potential, from treating human disease to saving endangered species.

Professor Azim Surani, Director of Germline and Epigenetics Research at the Gurdon Institute, University of Cambridge tells us about his journey of discovery.

Azim Surani in his office at the Gurdon Institute, Cambridge

Azim Surani in his office at the Gurdon Institute, Cambridge

I was a student of Bob Edwards, who later won the Nobel Prize for developing in vitro fertilisation. Bob asked me to work on embryo implantation but at the same time, allowed me the freedom to work on anything else too. I chose parthenogenesis, or ‘virgin birth’; the process in which an egg develops into an embryo without fertilisation by sperm – a male isn’t needed. It happens in many vertebrates, like frogs and fish, and I wanted to know whether mammals could do it too.

I was convinced that I was going to get a mouse to have a virgin birth on Christmas Day. Another scientist at Cambridge had managed to switch on the development of mouse eggs in the lab as if they’d been fertilised. It was like magic. I wondered if I could get them to develop to term. It never happened! I was so obsessed with the idea that my assistant and I did lots of experiments I’m quite embarrassed by now.

Hundreds of experiments later, I discovered that mammals need genes from both parents to make offspring. This was completely unexpected. Even though the maternal and paternal genes are virtually identical, they’re functionally different. It turns out that the maternal genome is more important for development of the embryo, and the paternal genome for the placenta.

Something was affecting gene expression during development. We later discovered there’s a kind of imprint, a memory of their parental origin, marked on the genomes at the germ line (egg and sperm) stage. The imprint is heritable after fertilisation and persists into adulthood. I called it genomic imprinting, and found it was caused by a process called DNA methylation as the heritable tag. Then, the field started to explode in many different directions.

We started looking for specific imprinted genes and underlying mechanisms. We found an imprinted gene expressed only from the paternal copy. A mutation of this copy led to abnormal maternal behaviour in mice. The mothers completely ignored their newborn pups and didn’t build a nest as they normally would. Around 200 imprinted genes have been discovered, with a range of functions.

Fourteen human diseases are now known to be linked to problems with genomic imprinting – the most common are Prader-Willi syndrome, Angelman syndrome and Beckwith-Wiedemann syndrome. Since identifying the genes involved, scientists have a better understanding of how they can be diagnosed. Because patients also carry an inactive copy of the imprinted gene, the goal is to reactivate this as a therapeutic option.

I later shifted my attention to the basic biology of germ line development. The germ cells are the precursors to eggs and sperm and are where these imprints, which we now call epigenetic marks, are erased and reestablished. We have discovered mechanisms that erase these marks, and mechanisms that put on new marks. This erasure resets the germ cells for the next generation and also ensures that any abnormal epigenetic marks don't get transmitted across generations.

Understanding the erasure process has important potential for addressing age-related diseases. Huge amounts of money are being spent trying to reprogram adult body cells, which also removes disease-causing abnormal epigenetic marks and restores the original state. If there are aberrant marks in body cells or germ cells, they’ll just be erased, and the cells will be rejuvenated.

There’s also excitement about the possibility of making egg and sperm cells from reprogrammed adult skin cells. That’s quite an amazing thought. It means that all our body cells are potential sources of new life. It sounds like science fiction, but it's already been done in mice, so in principle, it's possible.

This also raises the possibility of saving endangered mammals from extinction, like the northern white rhino in Kenya, where I’m from. Some zoos are already collecting skin cells from different species and freezing them in the hope this becomes possible in future.

I’m very curious about how genomic imprinting might be linked to the evolution of mammals. After the dinosaurs were wiped out around 65 million years ago, mammals evolved to live in so many different environments across the world – air, sea, desert and so on. I wonder if imprinting gave mammals the developmental flexibility to take these very diverse forms. I’m working on that idea at the moment.

This is what happens when you follow curiosity-driven research. It has taken a long time, and each step has been very challenging and slow. But that’s the exciting thing about science – I started with a single question, and now there’s a whole field spreading out in so many different directions.

THE SCIENCE IN BRIEF

What did Azim Surani discover? Through embryo manipulation experiments, Surani found that both female and male genes - from egg and sperm - are essential for normal development of the embryo in mammals. Even though the genes look identical, they’re not: offspring will not develop successfully from two sets of male genes, or two sets of female genes.

How did he discover it? It began with his student obsession with virgin birth - parthenogenesis - which can happen in non-mammals like fish and lizards but had never been seen in mammals. Others had tried to achieve it: mouse eggs had been activated and developed for several days but not into viable offspring.

What’s different about male and female genes in the embryo? Surani found that despite being virtually identical, the male and female genomes have different functions in mammalian development. Female genes are more important in forming the embryo, and male genes for forming the placenta that supports it.

What’s going on? He discovered that genomes are ‘tagged’ with chemicals - these epigenetic marks do not alter the genetic code. The tags are inherited from eggs and sperm at fertilisation and act like an on/off switch for specific genes depending on whether they come from the mother or the father. He called this genomic imprinting, and later worked out that the process happens in the precursor cells to eggs and sperm, called germ cells.

Why is this important? Termed ‘epigenetic inheritance’, this is an entirely new understanding of how some genes affecting mammalian development are regulated based entirely on their parental origin. The observation was unexpected as it challenges the long-standing laws of genetic inheritance, proposed by Gregor Mendel in 1865 and taught to generations of school children. It’s also important in understanding human diseases that involve mutations of these genomic imprints, which result in disturbances of growth and neuronal functions. Epigenetics is now an active and exciting area of research regarding development and disease.