̽��ֱ�� of Cambridge - Azim Surani

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

jg533 — Thu, 24 Oct 2024 15:05:35 +0000

Azim Surani has followed his curiosity for over half a century, rewriting science in the process.

Set up for life

cjb250 — Wed, 25 Nov 2020 08:13:14 +0000

We’re used to the idea that as adults we have some control over our destiny: what we eat and drink and how much we exercise can affect our health. But the risks of heart disease and diabetes can be programmed much earlier – even before we are born.

Similarities in human and pig embryos provide clues to early stages of development

cjb250 — Wed, 07 Jun 2017 17:00:39 +0000

In research published today in Nature, researchers at the ̽��ֱ�� of Cambridge and the ̽��ֱ�� of Nottingham demonstrate how pig embryos and human embryonic cells show remarkable similarities in the early stages of their development. By combining these two models, they hope to improve our understanding of the origins of diseases such as paediatric germ cell tumours and fetal abnormalities.

Primordial germ cells, the precursors of eggs and sperm, are among the earliest cells to emerge in human embryos after implantation, appearing around day 17, while the surrounding cells go on to form the rest of the human body. However, little is understood about how they originate. Currently, the law prohibits culture of human embryos beyond 14 days, which prevents investigations on this and subsequent events such as gastrulation, when the overall body plan is established.

Now, researchers have used a combination of human and pig models of development to shed light on these events. They have shown for the first time that the interplay between two key genes is critical for the formation of the germline precursors and that this ‘genetic cocktail’ is not the same in all species.

First, by using human pluripotent embryonic stem cells in vitro, scientists led by Professor Azim Surani at the Wellcome Trust/Cancer Research UK Gurdon Institute established a model that simulates genetic and cellular changes occurring up to gastrulation. Human pluripotent embryonic stem cells are ‘master cells’ found in embryos, which have the potential to become almost any type of cell in the body.

As these stem cells can be multiplied and precisely genetically manipulated, the model system provides a powerful tool for detailed molecular analysis of how human cells transform into distinct cell types during early development, and which changes might underlie human diseases.

̽��ֱ��work shows that when an embryo progresses towards gastrulation, cells temporarily acquire the potential to form primordial germ cells, but shortly afterwards lose this potential and instead acquire the potential to form precursors of blood and muscle (mesoderm) or precursors of the gut, lung and the pancreas (endoderm). ̽��ֱ��model also tells us that while the genes SOX17 and BLIMP1 are critical for germ cell fate, SOX17 subsequently has another role in the specification of endodermal tissues.

For an accurate picture of how the embryo develops, however, it is necessary to understand how cells behave in the three-dimensional context of a normal embryo. This cannot be achieved by studies on the most commonly used mouse embryos, which develop as egg ‘cylinders’, unlike the ‘flat-disc’ human embryos. Pig embryos, on the other hand, develop as flat discs (similar to human embryos), can be easily obtained, and are ethically more acceptable than working with non-human primate (monkey) embryos.

Researchers from the ̽��ֱ�� of Nottingham dissected whole flat discs from pig embryos at different developmental stages and found that development of these embryos matches with the observations on the in vitro human model, as well as with non-human primate embryonic stem cells in vitro. For example, pig germ cells emerge in the course of gastrulation just as predicted from the human model, and with the expression of the same key genes as in human germ cells. Human and pig germ cells also exhibit key characteristics of this lineage, including initiation of reprogramming and re-setting of the epigenome – modifications to our DNA that regulate its operations and have the potential to be passed down to our offspring – which continues as germ cells progress towards development into sperm and eggs.

̽��ֱ��combined human-pig models for early development and cell fate decisions likely reflect critical events in early human embryos in the womb. Altogether, knowledge gained from this approach can be applied to regenerative medicine for the derivation of relevant human cell types that might be used to help understand and treat human diseases, and to understand how mutations that perturb early development can result in human diseases.

Dr Ramiro Alberio, from the School of Biosciences at the ̽��ֱ�� of Nottingham, says: “We’ve shown how precursors to egg and sperm cells arise in pigs and humans, which have similar patterns of embryo development. This suggests that the pig can be an excellent model system for the study of early human development, as well as improving our understanding of the origins of genetic diseases.”

Dr Toshihiro Kobayashi in the Surani lab at the Gurdon Institute, adds: “We are currently prevented from studying human embryo development beyond day 14, which means that certain key stages in our development remain a mystery. ̽��ֱ��remarkable similarities between human and pig development suggest that we may soon be able to reveal the answers to some of our long-held questions.”

̽��ֱ��research was supported by Wellcome.

Reference
Kobayashi, T et al. Principles of early human development and germ cell program from conserved model systems. Nature; 7 June 2017; DOI: 10.1038/nature22812

Scientists have shown how the precursors of egg and sperm cells – the cells that are key to the preservation of a species – arise in the early embryo by studying pig embryos alongside human stem cells.

̽��ֱ��remarkable similarities between human and pig development suggest that we may soon be able to reveal the answers to some of our long-held questions

Toshihiro Kobayashi

Walfred Tang (Surani lab)

Developing human primordial germ cells (each small green and red cell is a PGC)

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Opinion: How close are we to successfully editing genes in human embryos?

Anonymous — Thu, 17 Dec 2015 11:31:23 +0000

An important international summit on human gene editing recently recommended that researchers go ahead with gene editing human embryos, but keep revisiting how and when such modifications would be appropriate in the clinic. ̽��ֱ��decision came after some scientists called for a moratorium on such research.

̽��ֱ��recommendation was always going to be controversial, with many people concerned that the technology, which could be used to prevent parents from passing on genetic diseases to their children, will be misused and lead to permanent changes in the human gene pool.

But how close are we – is there really reason to be concerned at this point?

Laboratory promise

Gene editing of the human germline – those cells that form the sperm and eggs and, from a fertilised egg, will generate every cell in the human body – is different from other types of genetic editing because changes in those cells will be inherited by future generations, to become a permanent change in the human make-up.

Working on human germline cells at the very earliest stages of the formation of an embryo, just after an egg has been fertilised and then implants itself in the womb, is of course impossible to do in a pregnant woman. In my lab, where our focus is on early development, we approach this research using mice and, more recently, by simply growing human cells in a culture dish. In this way we have managed to identify some of the earliest genetic events that “specify” a stem cell to become a germline cell.

At the same time the technology underpinning gene editing, such as the CRISPR/Cas9 – a fast, easy and unprecedentedly precise method for targeting edits to specific genes – is becoming widespread across science. Together with the new ways of studying germline cells in the lab, this is offering a real chance for scientists and the public to consider whether or not editing of the human germline has merit – before any harm can be done.

We can now create human “primordial germ cells”, the precursors to eggs and sperm, from embryonic stem cells. It is a delicate and time-consuming procedure, and the resulting cells do not survive beyond the very early stages of development – partly because we have yet to reproduce the conditions that they are designed to thrive in. What we have been able to show is that some of the earliest steps in the development of human primordial germ cells are different from those in mice. This is important as most of the previous results in this area have come from mouse models, indicating that such information cannot actually be wholly extrapolated to describe humans.

Last year, we also managed to generate primordial germ cells from adult body cells, such as human skin cells. We take body cells that have been programmed to revert back into stem cells, and add chemical factors to “re-specify” them as primordial germ cells.

It is possible to create gene-edited sperm in mice. But humans may be a different story. Gilberto Santa Rosa from Rio de Janeiro, Brazil/wikimedia, CC BY-SA

While these cells don’t survive long either, experiments have shown that introducing such cells into the testes and ovaries of in mice does allow them to continue their development and maturation into sperm and eggs. Remarkably, such mice were able to give birth to healthy offspring raising the prospect of reprogrammed skin cells creating living human beings. For that reason it certainly makes sense to carry out similar studies using primates. Further research might also make it possible to develop working sperm and egg cells entirely in a culture dish.

Finished blueprint?

Looking ahead, it is clear that there already is a potential template for editing the human germline. Genome-sequencing methods could also provide for additional checks to ensure that no inadvertent mutations or “off-target” effects have occurred during the editing procedures.

What’s more, if viable sperm and eggs could be grown in the lab from primordial germ cells, they could be used to generate fertilised embryos. Such “pre-implantation” embryos could also be further screened (as is routine now in the in-vitro fertilisation procedure) to ensure transfer to the womb of only those embryos that are free from specific mutations.

So how could this work in a clinic? Imagine combining the procedures in one patient, for example a woman with a disease-causing mutation who does not wish to pass this mutation to her child. Starting with a cell taken from her skin, this is reprogrammed to a primordial germ cell, in which the DNA is then edited to remove the mutated gene. ̽��ֱ��primordial germ cell is developed into an egg and used to create an embryo for IVF, to be screened and transplanted back into her womb. The child and its subsequent descendants would be free of the mutated gene.

There’s a reason why the summit carefully considered such massive implications and nevertheless recommended to pursue such research. Without making further gains in our knowledge about the fundamental processes in early germ cell and embryo development – starting with growing germ cells for longer in the culture dish – we will not know what we can and cannot safely achieve with the new gene-editing technologies. We are still some way from being able to contribute the necessary biological evidence to society’s debate about which, if any, of these technologies to pursue.

Azim Surani, Director of Germline and Epigenomics Research at the Gurdon Institute, ̽��ֱ�� of Cambridge

This article was originally published on ̽��ֱ��Conversation. Read the original article.

̽��ֱ��opinions expressed in this article are those of the individual author(s) and do not represent the views of the ̽��ֱ�� of Cambridge.

Azim Surani (Wellcome Trust/Cancer Research UK Gurdon Institute) discusses gene editing of the human germline.

Wellcome Images

A human embryo at the blastocyst stage, about six days after fertilization, viewed under a light microscope.

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Reprogramming of DNA observed in human germ cells for first time

cjb250 — Thu, 04 Jun 2015 16:00:31 +0000

However, the study, published today in the journal Cell, shows some regions of our DNA – including those associated with conditions such as obesity and schizophrenia – resist complete reprogramming.

Although our genetic information – the ‘code of life’ – is written in our DNA, our genes are turned on and off by epigenetic ‘switches’. For example, small methyl molecules attach to our DNA in a process known as methylation and contribute to the regulation of gene activity, which is important for normal development. Methylation may also occur spontaneously or through our interaction with the environment – for example, periods of famine can lead to methylation of certain genes – and some methylation patterns can be potentially damaging to our health. Almost all of this epigenetic information is, however, erased in germ cells prior to transmission to the next generation.

Professor Azim Surani from the Wellcome Trust/Cancer Research UK Gurdon Institute at the ̽��ֱ�� of Cambridge, explains: “Epigenetic information is important for regulating our genes, but any abnormal methylation, if passed down from generation to generation, may accumulate and be detrimental to offspring. For this reason, the information needs to be reset in every generation before further information is added to regulate development of a newly fertilised egg. It’s like erasing a computer disk before you add new data.”

When an egg cell is fertilised by a sperm, it begins to divide into a cluster of cells known as a blastocyst, the early stage of the embryo. Within the blastocyst, some cells are reset to their master state, becoming stem cells, which have the potential to develop into any type of cell within the body. A small number of these cells become primordial germ cells with the potential to become sperm or egg cells.

In a study funded primarily by the Wellcome Trust, Professor Surani and colleagues showed that a process of reprogramming the epigenetic information contained in these primordial germ cells is initiated around two weeks into the embryo’s development and continues through to around week nine. During this period, a genetic network acts to inhibit the enzymes that maintain or programme the epigenome until the DNA is almost clear of its methylation patterns.

Crucially, however, the researchers found that this process does not clear the entire epigenome: around 5% of our DNA appears resistant to reprogramming. These ‘escapee’ regions of the genome contain some genes that are particularly active in neuronal cells, which may serve important functions during development. However, data analysis of human diseases suggests that such genes are associated with conditions such as schizophrenia, metabolic disorders and obesity.

Walfred Tang, a PhD student who is the first author on the study, adds: “Our study has given us a good resource of potential candidates of regions of the genome where epigenetic information is passed down not just to the next generation but potentially to future generations, too. We know that some of these regions are the same in mice, too, which may provide us with the opportunity to study their function in greater detail.”

Epigenetic reprogramming also has potential consequences for the so-called ‘dark matter’ within our genome. As much as half of human DNA is estimated to be comprised of ‘retroelements’, regions of DNA that have entered our genome from foreign invaders including bacteria and plant DNA. Some of these regions can be beneficial and even drive evolution – for example, some of the genes important to the development of the human placenta started life as invaders. However, others can have a potentially detrimental effect – particularly if they jump about within our DNA, potentially interfering with our genes. For this reason, our bodies employ methylation as a defence mechanism to suppress the activity of these retroelements.

“Methylation is effective at controlling potentially harmful retroelements that might harm us, but if, as we’ve seen, methylation patterns are erased in our germ cells, we could potentially lose the first line of our defence,” says Professor Surani.

In fact, the researchers found that a notable fraction of the retroelements in our genome are ‘escapees’ and retain their methylation patterns – particularly those retroelements that have entered our genome in our more recent evolutionary history. This suggests that our body’s defence mechanism may be keeping some epigenetic information intact to protect us from potentially detrimental effects.

Reference
Tang, WWC et al. A unique gene regulatory network resets the human germline epigenome for development. Cell; 4 June 2015

A team of researchers led by the ̽��ֱ�� of Cambridge has described for the first time in humans how the epigenome – the suite of molecules attached to our DNA that switch our genes on and off – is comprehensively erased in early primordial germ cells prior to the generation of egg and sperm.

[ ̽��ֱ��information on our DNA] needs to be reset in every generation before further information is added to regulate development of a newly fertilised egg. It’s like erasing a computer disk before you add new data

Azim Surani

Thomas Au

Reset button (edited)

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Professor Azim Surani awarded Jawaharlal Nehru Fellowship by the Government of India

bjb42 — Fri, 21 Feb 2014 16:13:46 +0000

̽��ֱ��newly instituted Fellowship enables eminent scientists to associate with Indian research centres and conduct research in the country for a 12 month period over 3 years. Professor Surani’s will be hosted for the fellowship period by the Institute for Stem Cell Biology and Regenerative Medicine (InStem) in Bangalore.

Former Director of Instem and current Secretary to India’s Department of Biotechnology Professor K VijayRaghavan welcomed the news: “Azim Surani is one of the world’s leading biologists, a pioneer in the study of the developmental programming of gene expression. Having Azim more frequently on campus will only enhance the vibrant intellectual environment at Instem. His understated and calm approach hides a powerhouse of ideas and an incisive logical approach to tackling the greatest of problems.”

̽��ֱ��Indian Prime Minister, Dr Manmohan Singh, announced at the 101st Annual Session of the Indian Science Congress that Professor Azim Surani of the Gurdon Institute has been awarded the prestigious Jawaharlal Nehru Fellowship by the Government of India’s Department of Science and Technology.

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Scientists discover how epigenetic information could be inherited

hps25 — Fri, 25 Jan 2013 13:25:47 +0000

New research reveals a potential way for how parents’ experiences could be passed to their offspring’s genes. ̽��ֱ��research was published today, 25 January, in the journal Science.

Epigenetics is a system that turns our genes on and off. ̽��ֱ��process works by chemical tags, known as epigenetic marks, attaching to DNA and telling a cell to either use or ignore a particular gene.

̽��ֱ��most common epigenetic mark is a methyl group. When these groups fasten to DNA through a process called methylation they block the attachment of proteins which normally turn the genes on. As a result, the gene is turned off.

Scientists have witnessed epigenetic inheritance, the observation that offspring may inherit altered traits due to their parents’ past experiences. For example, historical incidences of famine have resulted in health effects on the children and grandchildren of individuals who had restricted diets, possibly because of inheritance of altered epigenetic marks caused by a restricted diet.

However, it is thought that between each generation the epigenetic marks are erased in cells called primordial gene cells (PGC), the precursors to sperm and eggs. This ‘reprogramming’ allows all genes to be read afresh for each new person – leaving scientists to question how epigenetic inheritance could occur.

̽��ֱ��new Cambridge study initially discovered how the DNA methylation marks are erased in PGCs, a question that has been under intense investigation over the past ten years. ̽��ֱ��methylation marks are converted to hydroxymethylation which is then progressively diluted out as the cells divide. This process turns out to be remarkably efficient and seems to reset the genes for each new generation. Understanding the mechanism of epigenetic resetting could be exploited to deal with adult diseases linked with an accumulation of aberrant epigenetic marks, such as cancers, or in ‘rejuvenating’ aged cells.

However, the researchers, who were funded by the Wellcome Trust, also found that some rare methylation can ‘escape’ the reprogramming process and can thus be passed on to offspring – revealing how epigenetic inheritance could occur. This is important because aberrant methylation could accumulate at genes during a lifetime in response to environmental factors, such as chemical exposure or nutrition, and can cause abnormal use of genes, leading to disease. If these marks are then inherited by offspring, their genes could also be affected.

Dr Jamie Hackett from the ̽��ֱ�� of Cambridge, who led the research, said: “Our research demonstrates how genes could retain some memory of their past experiences, revealing that one of the big barriers to the theory of epigenetic inheritance – that epigenetic information is erased between generations – should be reassessed.”

“It seems that while the precursors to sperm and eggs are very effective in erasing most methylation marks, they are fallible and at a low frequency may allow some epigenetic information to be transmitted to subsequent generations. ̽��ֱ��inheritance of differential epigenetic information could potentially contribute to altered traits or disease susceptibility in offspring and future descendants.”

“However, it is not yet clear what consequences, if any, epigenetic inheritance might have in humans. Further studies should give us a clearer understanding of the extent to which heritable traits can be derived from epigenetic inheritance, and not just from genes. That could have profound consequences for future generations.”

Professor Azim Surani from the ̽��ֱ�� of Cambridge, principal investigator of the research, said: “ ̽��ֱ��new study has the potential to be exploited in two distinct ways. First, the work could provide information on how to erase aberrant epigenetic marks that may underlie some diseases in adults. Second, the study provides opportunities to address whether germ cells can acquire new epigenetic marks through environmental or dietary influences on parents that may evade erasure and be transmitted to subsequent generations, with potentially undesirable consequences.”

Research reveals the mechanism of epigenetic reprogramming.

Our research demonstrates how genes could retain some memory of their past experiences, revealing that one of the big barriers to the theory of epigenetic inheritance - that epigenetic information is erased between generations - should be reassessed.

Jamie Hackett

Amy Loves Yah from Flickr

Beakers

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Germ cells: the route to immortality

bjb42 — Wed, 01 Apr 2009 15:28:15 +0000

A fertilised egg is potentially immortal since it develops into a new organism that, in turn, can give rise to an endless series of generations. ̽��ֱ��precursors of sperm and eggs, known as germ cells, provide this enduring link between generations because they transmit the parents’ genetic information to the offspring. Precisely how these cells become equipped to reproduce a new organism – and the remarkable erasing and reprogramming steps that happen during this process – is being studied by Professor Azim Surani’s research group in the Wellcome Trust/Cancer Research UK Gurdon Institute, with funding from the Wellcome Trust and the Biotechnology and Biological Sciences Research Council (BBSRC).

Backing-up the blueprint

Even as the embryo implants in the lining of the womb during pregnancy, a founding population of germ cells is already being set aside within the embryo for the next generation. It’s very important that these cells maintain the ability to form every cell type within the organism – an attribute known as pluripotency and one that is quickly lost from those cells that develop into the rest of the body (skin, neurones, muscle and so on). Studies in Professor Surani’s group have discovered that these primordial germ cells develop in response to a ‘master regulator’ of germ cell fate called Blimp1. This initiates a special germ cell programme that at the same time represses all the other potential cell fates in these cells, leaving intact the blueprint for creating any cell in the body.

Wiping the disc clean

After Blimp1 has halted the march towards development into body cells, the germ cells then proliferate and migrate into fetal gonads, which develop independently at another site in the embryo to form either testes or ovaries. Here, one of the most extraordinary of events occurs that is rather like wiping a hard disc clean and then reloading it with either a maternal or a paternal operating system.

̽��ֱ��critical ‘re-setting’ event wipes out all the pre-existing information and ‘imprints’ that are normally associated with the genetic blueprint that carries the instructions necessary to form the whole organism. This associated information, known as epigenetic modification, is usually required to interpret the genetic information appropriately so that the right genes are selected for expression at the right time during critical cell fate decisions. ̽��ֱ��modifications are ‘imprinted’ and heritable, to denote their maternal or paternal origin.

What the researchers at the Gurdon Institute have discovered is precisely how the erasure process wipes out all the pre-existing epigenetic information and imprints. This leaves the genetic information intact in preparation for new instructions and imprints to be laid down on top of the genetic information – a process that occurs during development of the eggs and sperm in the growing fetus.

How to make eggs and sperm

Our understanding of these processes has now reached such a level that it is possible to make germ cells directly from pluripotent embryonic stem cells, or even from body cells such as skin cells. This naturally raises the prospect that sperm and eggs could be developed directly from body cells in a culture dish. Such innovations might provide new opportunities for applications in reproductive medicine, including exploration of the basis for certain forms of infertility or the underlying causes of cancers such as testicular tumours. But they also raise important ethical issues that will need to be addressed hand-in-hand with progress in the field.

For more information, please contact the author Professor Azim Surani (a.surani@gurdon.cam.ac.uk) at the Wellcome Trust/Cancer Research UK Gurdon Institute. This research was published in Nature (2008) 452, 877–881 and (2005) 436, 207–213.

How do cells become equipped to generate a whole new organism?

Our understanding of these processes has now reached such a level that it is possible to make germ cells directly from pluripotent embryonic stem cells.

Nature (2005), 436, 207-213

Primordial germ cells

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