All posts by sangerinstitute

From the Wellcome Sanger Institute, a charitably funded genomic research organisation

Chernobyl Dogs
Sanger LifeSanger Science

Chernobyl: chasing a ‘catching’ cancer

By: Alison Cranage, Science Writer at the Wellcome Sanger Institute
Date: 06.12.18

Chernobyl_placement_Holek_WikimediaCommons_300On 24th April 1986, a reactor at the Chernobyl power plant in the Ukraine exploded. It was the worst nuclear accident the world has ever seen.

Radioactive material plumed, contaminating the air, soil and water. Effects are still seen today, 32 years later and hundreds of miles away, where land in parts of Europe is deemed unsafe for farming.

The number of people who died as a result of the disaster may never be known. It is thought that thousands of lives have been lost. Some died from acute radiation sickness immediately after the blast; others, later, from thyroid cancer caused by exposure to radiation.

After the explosion, over 90,000 people were evacuated from hundreds of towns and communities in the vicinity of the plant. They had to leave everything behind, including their pets. The area lay barren for many years as high radiation levels meant nothing could grow.

Chernobyl’s Exclusion Zone

Today, a 200 km chain-link metal fence surrounds the plant – creating an ‘exclusion zone’ stretching for 30km in every direction. Radiation levels have returned to near normal in most places, though certain ‘hot spots’ remain. Forests have re-established themselves, swallowing the abandoned towns and villages.

People have returned to the zone too – some 3,500 work there, as security guards or in offices that, remarkably, still surround the power plant. Animals have also returned, including bears, wolves and smaller mammals. Some animals never left, including the descendants of the pet dogs that people had to leave behind when they fled.

The dogs, resembling German Shepherds, are fed by visitors, workers and the security guards. Despite this kindness, the animals face many challenges. During the harsh winters, they seek shelter in the abandoned buildings. They are hunted by wolves in the forests and exposed to rabies by wild animals. Though puppies seem to thrive, it is hard to find a dog more than a few years old.

Alex Cagan, post-doctoral researcher at the Wellcome Sanger Institute, joined a trip to Chernobyl in June 2018. Run by the Clean Futures Fund (CFF), he travelled with a team of vets to visit the abandoned dogs. He was looking for an unusual type of cancer.

Catching cancer

Transmissible cancer is a strange form of the disease. Unlike any other type of cancer it is not caused by an individual’s own cells growing uncontrollably. It’s an infectious cancer – it’s a cancer dogs can catch.

It first arose in an animal who lived about 8,000 years ago. Cells from this animal, termed the ‘founder dog’, were passed on to other dogs. The cells somehow survive, evading the immune system of new animals, continuing to grow and form tumours.

The tumours are contagious, sexually transmitted, and have spread around the world. Genomic analysis has shown that wherever there are populations of stray dogs – from the deserts of Africa to the Himalayas to the Australian Outback – there are these tumours. Each one carries descendants of the cells from the founder dog.

In essence, the tumour is a parasite, being passed from host to host. Little is understood about its biology – for example no-one knows exactly how it escapes the immune system. Alex is working with Elizabeth Murchison, a group leader at the University of Cambridge who studies transmissible cancers. The aim was to collect samples for genomic analysis – to see if the radiation has any effects on the cancers.

Caring for the dogs of Chernobyl

Clean Futures Fund make several trips a year to care for the animals. The vets check the dogs, treat any injuries and neuter them, to help control the population. Researchers from around the world, studying the unique environment and the effects of radiation on animal populations, join them.

Alex joined the team in the town of Slavutych, just outside the exclusion zone. Travelling by train, and then in an old Soviet truck, they entered the exclusion zone every day, setting up makeshift clinics in old barracks or buildings.

Despite the 30 degree summer heat, everyone entering the zone is required to wear long sleeves and trousers to cover as much skin as possible, as a precaution. All visitors are given a small Geiger-counter to wear around their neck – constantly monitoring the radiation levels. There’s no eating or drinking allowed out in the open, to minimise the risk of radiation exposure. People are screened on the way out of the zone to check radiation levels on their body. If they’re too high, the advice is to take a shower.

“I was worried at first,” said Alex. “But I was with radiation experts and they weren’t, so my mind was put at ease. The amount of background radiation there now, in most places, is the same as you’d get taking a trans-Atlantic flight. The risks are really low.”

“You do see the odd anomaly. There was a sink in one of the buildings with a mirror above it. Someone had written ‘Danger: Do not touch sink bowls. Handles ok’. If you pointed your Geiger counter at it, the readings were massive.”

Each person in the team had a clear job. While the dog catchers set off to find the strays, the vets set up the clinics. Alex took tissue samples from the testes of the neutered animals.

The curious case of the contagious cancer

In the 200 dogs he saw over two weeks, Alex didn’t find a single case of transmissible cancer. Elizabeth was surprised to hear the news. “We see transmissible cancer in dogs all around the world. We find it almost everywhere there are free roaming dog populations. We don’t know why the dogs in Chernobyl don’t have it.”

“There are several theories. Most likely it is probably by chance. They are an isolated population, so perhaps they’ve never come across it, or maybe the disease used to be in the population but has now disappeared. This is really just speculation, but it might be something unique about this dog population, perhaps their immune systems are more able to fight it off somehow. But as far as we know there is nothing different about them compared to other Ukrainian dog populations.”

“We know the cancers are very sensitive to radiotherapy – and so the wildest theory is that maybe the exposure to radiation over the years have been protective.”

“The wildest theory is that maybe the exposure to radiation over the years have been protective”

The dog transmissible cancer normally doesn’t grow if its DNA is broken, or exposed to DNA damaging agents. This is good news for any dogs who do have it – it is easily treated with chemotherapy and the vets had doses ready.

“We will probably never know why it’s not there.” Elizabeth is going to keep in touch with CFF, in case the vets do spot any cases.

If they find it, her team is particularly interested in the ‘mutational signature’ of the DNA in the tumour cells. These are patterns of change in a DNA sequence. Anything that causes damage to DNA, like tobacco smoke, or radiation, causes a unique pattern of change. Radiation causes a particular kind of damage to DNA – double stranded breaks.

The team were particularly keen to study cancers that might have been exposed to radiation. Would they be able to spot tell-tale signs of the Chernobyl explosion in the DNA? It would tell them how the cancer responds to DNA damage and different levels of radiation.

From Chernobyl to Tasmania (via Cambridge)

Elizabeth’s research into transmissible cancers continues back in Cambridge. Her goal is to look at the genomic diversity of transmissible cancers around the world. As well as being affected by external agents, the transmissible cancer genome evolves over time, accumulating changes. By tracking these changes, her team is able to construct an evolutionary tree – showing how related each cancer is to another, and when it was passed on.

1024px-Tasdevil_largeHer team are also studying the effects of another infectious cancer – Tasmania Devil Facial Tumour Disease. Spread in the animals’ saliva when they bite each other’s faces, the cancer is a huge threat to the devils. It has decimated their numbers, affecting up to 65 per cent of the population in Tasmania, Australia.

When Elizabeth was based at the Sanger Institute, she sequenced the genome of the Tasmanian devil transmissible cancer. She found that, again, the disease first arose from the cells of a single animal – in this case, a female Tasmanian devil. The animal has been dubbed ‘The Immortal Devil’, because although she died over 20 years ago, her DNA lives on in the contagious cancer cells she spawned. Elizabeth’s aim is to eliminate the disease.

Mutational DNA Signatures

Alex’s visit was driven by curiosity and he hopes it will deliver some useful insights. He took 20 DNA samples from the dogs for his group’s cancer work back at the Sanger Institute. Their team is interested in mutational signatures – although they will be looking for DNA damage in healthy, non-cancerous cells. DNA analysis of the healthy dogs will also give information about the population as a whole. For example, it may reveal if the dogs have mated with the wolf population. And it may give clues as to why the dogs only live for a few years.

Chernobyl is a unique location for tragic reasons. But it might be able to help Alex’s team find out more about the impact of radiation on the genome. A huge amount is unknown, said Alex. “It is the first time that complete genomes have been sequenced from any animals living in the exclusion zone. We don’t know what we will find.”

Find out more

Alex Cagan is speaking about his work at the next ‘Genome Lates’ event on Friday 7th December at the Wellcome Genome Campus in Cambridge.

About the Author

Alison Cranage is the Science Writer at the Wellcome Trust Sanger Institute

Human Embryo Editing: science fiction or science fact?
Influencing PolicySanger Life

Human Embryo Editing: science fiction or science fact?

By: Anna Middleton, Head of the Society and Ethics research group at the Wellcome Genome Campus Connecting Science
Date: 29.11.18

“As scientific knowledge advances and societal views evolve, the clinical use of germline editing should be revisited on a regular basis”

2015 Organizing Committee of the First International Summit on Human Genome Editing

And here we are at the end of 2018, ‘revisiting’ this for real. I’m writing this while sitting in the audience in Hong Kong at the Second International Summit on Human Genome Editing, funded by the Royal Society, National Academy of Sciences, National Academy of Medicine and the University of Hong Kong. As an invited presenter on the public responses to genomics I’m excited to be sitting amongst global representatives from science, medicine and ethics.

The first thing that strikes me is the overwhelming presence of media in the auditorium, all excited by the announcement yesterday of the ‘first’ edited embryos to have been born, apparently delivered a few weeks ago.  The veracity of this is still very much a topic of debate across the media and scientific establishment.  There are many gaps and unusual elements to the announcement that call for caution and further detail.  But in the busy coffee breaks, the chat focuses on the ‘disbelief and horror’, and ‘how did he manage to do this without ethical regulation?’ There is concern in the air about the ‘ease’ with which the scientist could persuade a series of patients undergoing IVF to allow him to edit their healthy embryos. Prof He Jiankui, an associate professor at a Shenzhen university (https://theconversation.com/rogue-science-strikes-again-the-case-of-the-first-gene-edited-babies-107684) claims to have edited a single gene that may offer some level of protection against future HIV infection.

The editing of embryos with intention of implantation and pregnancy, is illegal in many countries including the UK, all of the EU and the US.  A change in the law is not going to happen any time soon, but I guess that may give time for the scientific research and ethical enquiry to reach some level of consensus on what could and should be offered.

What seems to be generally agreed amongst the audience of delegates at this Summit is that the science just isn’t there yet to guarantee that there would be no downstream effects of editing one gene and either inadvertently editing another at the same time, or causing a disruption of an unexpected pathway leading to the creation of disease. So, what cannot be guaranteed is that these newly edited children won’t be susceptible to other serious health problems. We are reassured by Prof He that he will cover the medical bills for these children up to the age of 18.

Such reassurance on medical bills doesn’t really cover all of the implications and issues that Prof He’s announcement presents. The Nuffield Council on Bioethics previously reported in ‘Genome Editing and human reproduction report’ (July 2018): ‘We can, indeed, envisage circumstances in which heritable genome editing interventions SHOULD be permitted’. But the caveat was that such a possibility would only come after appropriate public debate.

At the Summit, one of the leaders in the field,  Prof George Daley, from Harvard Medical School reassured his audience that the current ‘mishap’ should not put us off striving for delivering the best science together with ethical frameworks to offer oversight of embryo editing. He asserts: ‘we need a well-defined translational pathway’ so that in the future we could offer embryo editing clinically for those that need it.

The science and the ethics of these issues have a long way to go. But already Prof He’s claim is opening up another level of debate.

Prof Daley was also asked about  ‘other clinical pathways that could be used instead of embryo editing, what about pre-implantation genetic diagnosis?’ He replied that he envisions in the future that embryo editing will be easier than PGD; and editing of gametes before fertilisation will become a reality, thus both of these may become the treatment of choice.

So there we have it. At this Summit on Genome Editing, we appear to be heading towards a future where editing of embryos in clinical practice to patients and families is technically possible. At the Summit we hear impassioned calls from patient groups, for example, the Sickle Cell Disease Community who are embracing genome editing, primarily in somatic testing, but they were not ruling out work in embryos.

There are repeated calls from the audience for ‘consensus’ and ‘acceptability’ from the public. These calls are fleetingly mentioned without real thought or understanding of just how hard this is to do. With an average reading age of 10 in the UK and 85 per cent of people having never heard of the word ‘genome’ before, we have a long way to go to socialise this enough to enable meaningful debate.  That’s not to say we shouldn’t do it, we absolutely should, but instead of just imagining this happens by osmosis, we should adequately value, resource and support the communication research to enable this to happen appropriately.

The summit organisers have put out a statement on the issue, which concludes that, currently “the scientific understanding and technical requirements for clinical practice remain too uncertain and the risks too great to permit clinical trials of germline editing.”

The question of if this is fact or fiction will become clear in coming days and weeks. What is clear is that there is an urgent need for the community to reach some conclusions on the issues raised. And the clock is ticking.

About the Author

Anna Middleton is Head of the Society and Ethics research group at the Wellcome Genome Campus Connecting Science

Dr Cordelia Langford wins BioBeat award
Sanger Life

Dr Cordelia Langford wins BioBeat award

By: Alison Cranage, Science Writer at the Wellcome Sanger Institute
Date: 14.11.18

Cordelia’s love of science started early, as she visited her father at work in his research laboratory.

“From a very young age I went into his lab – and I was intrigued by the science happening there. He was an electron microscopist and I was fascinated with the inner functioning of cells. That’s something that’s stayed with me.

The Medical Research Council - Laboratory of Molecular Biology (known as the MRC-LMB) as it was until it was rebuilt in 2013. Image credit: Jynto, Wikmedia Commons

The Medical Research Council – Laboratory of Molecular Biology (known as the MRC-LMB) as it was until it was rebuilt in 2013. It was here that Cordelia’s love of science was sparked. Image credit: Jynto, Wikmedia Commons

“My mother was head of science at a senior school in Cambridge. Between them they fostered this interest in science. When I was 16 I had the opportunity of a holiday job at the MRC Laboratory of Molecular Biology. I realised I had a talent for technical work – everything started from there. I wanted to become qualified, but I didn’t follow the traditional route. All of my post A-level qualifications were done whilst I continued working. I joined the Sanger Centre as an undergraduate research assistant in 1994, when the Sanger was less than a year old, working on the human genome project.”

Since then, the science and the technology to deliver cutting edge genomic research have been constantly evolving. That first human genome sequence took 13 years to complete. Now, the Sanger Institute sequences the equivalent of a human genome every 24 minutes.

“I am so inspired by the mission of the Sanger Institute. Part of what drives me is wanting to move our science forwards in the delivery of what does truly feel like research that is changing the lives of people. Having an understanding of the Sanger’s ambitious scientific goals, and knowing everything that’s going on in terms of technical development, then being able to translate that into new pipelines and new platforms is very satisfying.

“And I get to work with some extraordinary, talented people.”

Cordelia now leads a team of 300 scientists and the delivery of all the scientific operations at the Sanger Institute. This includes all the data production pipelines – from the animal facility, to the production and maintenance of cells and tissues used in research, and all of the DNA and RNA sequencing facilities.

She described some of the support she’s had throughout her career.

“In the main it’s been training. Technical skills, but more importantly skills that you need to become a manager of people and operations. I still reflect on a training course I went on for presentation skills, very early on in my PhD. I still use those techniques for presentations today. I feel as though there has been a sustained investment in helping me to hone my skills and I feel like I’ve never stopped learning.”

The UK Biobank vanguard project (to sequence the genomes of the first 50,000 UK Biobank volunteers) is being overseen by the Sanger Institute's Cordelia Langford after successfully led the Sanger's bid to carry out the work

The UK Biobank Vanguard project (to sequence the genomes of the first 50,000 UK Biobank volunteers) is being overseen by the Sanger Institute’s Cordelia Langford after successfully she led the Sanger’s bid

Cordelia described one of the most exciting areas of her work at the moment – UK Biobank. The project is following the health and well-being of 500,000 volunteer participants, providing health information to researchers from around the world. She recently led the Institutes successful bid to sequence 50,000 whole genomes as part of the project.

“It’s the end point that’s the main excitement. It’s a mind blowing resource that’s been built up. The gathering of the information, the consent of the participants and the richness of the dataset – it’s really only recently sunk in how impactful this is around the world. It’s openly available for researchers to access. The fact that my teams are able to generate the icing on the cake with full genome sequence data to add to that is very rewarding.”

biobeat18_moversCordelia was recognised in the collaboration category of the BioBeat award. Much of her work spans across different teams within the institute, as well as between institutes around the world. She also co-ordinates partnerships with commercial companies – those that supply the DNA sequencing machines and associated technologies, for example. Recently she brought together thought leaders, suppliers and partners in DNA sequencing for a unique meeting to describe the future strategy for genomic technology. The aim was to enable the research community to work together with technology suppliers to shape a road map for the future.

“I believe that revolutionary collaborative exchange – breaking the boundaries between researchers, innovators and suppliers – is key. It will enable us to deliver transformative science and tackle global challenges.” says Cordelia.

The BioBeat award celebrates women in science and bio-business. We discussed some of the issues that face women in science today.

Dr Cordelia Langford, Head of Scientific Operations at the Wellcome Sanger Institute, was named as one of Biobeat18's top movers and shakers

Dr Cordelia Langford, Head of Scientific Operations at the Wellcome Sanger Institute, was named as one of BioBeat18’s top movers and shakers

“I feel as though I’ve experienced a lot of what is often spoken about as challenges faced by women. A perception of glass ceilings, of being treated differently. People have not always encouraged my growth, or supported positive outcomes in certain situations.

“I think some of those experiences, or unintentional comments, have made me feel inhibited at times, and perhaps hindered me. I’ve sometimes had a feeling of imposter syndrome, and I’ve realised it’s not all from within. Getting through that barrier is tough, psychologically. But when it’s not there it’s such an amazing and empowering feeling. I feel less inhibited now, more able to play to my strengths as a leader, and to be me.

“There is a gender imbalance in science, as elsewhere in society. I believe there is more work to do to change the perception that appointing women to senior positions is tokenism. Women should be truly and equally recognised for their skills and achievements and should have every opportunity to reach their potential.

“I want to be part of the solution, clearing the way for junior staff so they feel there aren’t so many ceilings to smash. My past experiences, and my leadership skills, can help me to do .”

“I’m delighted to be taking over the chair of the Athena SWAN working group here at the Sanger Institute from 2019. We are committed to advancing gender equality in terms of representation, progression and success for all.”

With such a broad level of experience, it’s interesting to hear what advice she’d give for young researchers.

Cordelia_advice“Something that has been a golden thread for me is that I’ve been really clear about what I think I can achieve. I’ve thought about how I might travel towards my career goals. I’ve always kept that in mind. I’ve been patient, gathered my experience and taken job opportunities.

“Something I advise people is to have an open mind about opportunities. Don’t always feel you have to climb the ladder. Sometimes a sideways move might actually be building experience and knowledge that may be a spring board to a more senior role, if that’s what people are after.

“A solid group of mentors is invaluable. And something I’ve learnt more recently is the importance of balancing work with life. I know that I’m much more effective if I have time clear to be able to think, to reflect on what’s important here at work, and make sure I focus on the priorities.”

Finally, we talked about winning the BioBeat award. “I was privileged to be approached and to be included among such an outstanding group of leaders -it’s so gratifying and I feel very proud.” Cordelia said.

She also acknowledged all of the staff in her teams. “They are hugely inspiring, with diverse experiences and views. Everyone comes together to work towards joint goals.”

Her teams remain at the forefront of genome science. They have embraced and developed new technologies – for example in sequencing RNA from single cells, to allow the discovery of its activities. They are also enabling the high throughput sequencing and analysis needed for so many of the research projects at Sanger.

Golden Eagle - the first UK species to have its DNA read by the Sanger Institute as part of its 25 genomes for 25 years project. Image credit: Martin Mecnarowski, Wikimedia Commons.

Golden Eagle – the first UK species to have its DNA read by the Sanger Institute as part of its 25 genomes for 25 years project. Image credit: Martin Mecnarowski, Wikimedia Commons.

The next big challenge for Cordelia’s teams is the Darwin Tree of Life Project, where the Institute will be sequencing all animal, plant, fungi and protozoan life in the UK – some 66,000 species. The project brings huge technical challenges, in sample collection, DNA extraction and preparation, sequencing new genomes and assembling them – and doing all that at scale. The project has captured her imagination.

“It was fantastic to be able to sequence the golden eagle – it’s such an iconic bird. And the genome we published was very good quality. There are undoubtedly going to be a lot of surprises as we sequence thousands of new species, we’re going to learn a lot, and it’s going to be an exhilarating and impactful project.”

About the Author

Alison Cranage is the Science Writer at the Wellcome Sanger Institute

Links:

Darwin Tree of Life: focusing on fungi and probing plants. Snapshots from the Fungarium at The Royal Botanic Gardens, Kew. Image Credit: The Royal Botanic Gardens, Kew
25 Genomes

Darwin Tree of Life: focusing on fungi and probing plants

By: Alison Cranage, Science Writer at the Wellcome Sanger Institute
Date: 12.11.18

Botanic gardens - such as Darwin Tree of Life Project partner Kew Gardens - contain approx 1/3rd of all plant life on earth

Darwin Tree of Life Project partner, The Royal Botanic Gardens, Kew has an estimated 1.25 million dried fungi specimens

All our lives depend on plants and fungi. Genome sequencing is beginning to uncover their incredible diversity, yet only a tiny fraction of the millions of species which inhabit the planet have been analysed. The Earth BioGenome Project, which aims to sequence the DNA of all complex life, will be cataloguing and sequencing all plants and fungi, together with all animals and protozoa.

The Royal Botanic Gardens, Kew is home to the largest and most diverse collection of plants and fungi in the world. They are a key partner in the Darwin Tree of Life Project to sequence the genomes of all eukaryotic life in the UK – providing scientific expertise and extensive plant and fungi collections.

The genomes of all fungi

Fungal Facts

Fungal Facts

Baker’s yeast (Saccharomyces cerevisiae) was the first eukaryote to have its whole genome sequenced back in 1996. Since then, over 1,500 species of fungi have had their genome sequenced. There are about 140,000 species known to science, with an average of 2,000 new species described every year. The total number of fungi species is estimated to be between 2.3 and 3 million.

Genome sequences are already helping people capitalise on some of the unique properties of fungi. They are widely used in industry for the large-scale production of a diverse array of chemicals – from food to pharmaceuticals.

We spoke to Dr. Ester Gaya, Senior Mycology Researcher at Kew Gardens, about some of the untapped resources of fungi.

“Many antibiotics come from fungi. Researching fungal diversity could lead to the discovery of new sources of antibiotics and medicines.

“In industry the genomes of several fungal species are being studied because of their ability to produce ‘mycodiesel’. It may be we can produce fuel sustainably and on an industrial scale.

“There is also research into how we can use fungi for bioremediation.  Some species have the ability to consume and break down environmental pollutants – so they could be used to clean up oil spills, for example.”

Dr Ester Gaya, Research Leader in Comparative Fungal Biology at The Royal Botanic Gardens, Kew. Photographed in the organisation's historical archive. Image Credit: The Royal Botanic Gardens, Kew

Dr Ester Gaya, Research Leader in Comparative Fungal Biology at The Royal Botanic Gardens, Kew. Photographed in the organisation’s historical archive. Image Credit: The Royal Botanic Gardens, Kew

Not all fungi are beneficial. Many species are harmful to humans. For example Pneumocystis jirovecii causes a type of pneumonia and Candida albicans causes thrush. These, together with hundreds of other harmful species, have had their genomes sequenced – helping researchers design better treatments and surveillance systems.

Other fungi species target plants, including key food crops. Researchers are studying their genomes to understand how their pathogenicity works – understanding which genes are active, will enable researchers to develop new ways to tackle them and improve crop yield.

Inside the Fungarium

This slideshow requires JavaScript.

Tasty genomes

Plants underpin all aspects of our everyday life – from the food we eat to the air we breathe. Like fungi, only a tiny fraction of plant species on the planet have had their genome sequence determined.

Most plant species with genomes sequenced to date are crops, including the major cereals – rice, wheat and maize, as well as fruits and vegetables. Commercially important crops that make our favourite drinks like coffee, grapes and hops have also had their genomes sequenced. Studying these genomes helps enhance yield, as well as shedding light on the mechanisms of taste and quality.

Studying the genomes of relatives of crop species is also important. These plants harbour important genetic diversity, often lost in the domesticated crops that dominate world agriculture.  75 per cent of the world’s food supply depends on just 12 species of plants. Their wild relatives harbour essential genetic diversity which can be used for breeding resilience to disease and to climate change.

Beyond food

Plants are a hugely diverse group of organisms, from trees with 5,000 year lifespans to unicellular green algae. Their uses are equally diverse, from medicines to biofuels and materials.

Plant sciences have a vital role in addressing some of the most critical global challenges, such as climate change and food security. Plant science can provide the fundamental research required to protect biodiversity, as well as mitigate and adapt to climate change. Whole genome sequence data will enable researchers to drive the understanding of plant development and evolution and their potential contribution to sustainable agriculture. And new, detailed insights from genome sequences may help us understand medicinally important compounds.

Challenges

How modern life is built on fungi

How modern life is built on fungi

There is no doubt the project comes with challenges. The quality and amount of material available for DNA sequencing will be an issue. This is particularly a problem for microscopic fungi, as many cannot be cultivated outside their natural habitat. This makes it difficult to gather enough material for DNA sequencing. Getting good quality DNA from historical plant and fungal samples, like those housed at Kew, may also be difficult – though it is an area that is rapidly improving.

There are an estimated 1,500 plant species native to the UK, with a total of 400,000 around the world. Nearly all UK species have been catalogued and have seeds stored by Kew. The project is likely to discover new species of both plants and fungi though.

“In fungi there are what we call ‘dark taxa’ ” says Dr. Gaya. “They’re hidden to the naked eye. And before the advent of DNA sequencing we didn’t have the tools to discover them.”

Scientists at the University of Exeter discovered a whole new phylum of fungi in 2011 – it was a whole new branch, right at the base of the fungal tree of life. The microscopic fungi were found living in a pond on the University campus.

We have only just started to scratch the surface of these remarkable groups of organisms.

Dr. Gaya is particularly interested in the genomes of these lichenised fungi – whose orange pigment acts like a sunscreen, protecting them from UV damage and allowing them to grow in some of the driest places on Earth

Dr. Gaya is particularly interested in the genomes of these lichenised fungi – whose orange pigment acts like a sunscreen, protecting them from UV damage and allowing them to grow in some of the driest places on Earth. Image Credit: The Royal Botanic Gardens, Kew

About the Author

Alison Cranage is the Science Writer at the Wellcome Sanger Institute

Links:

Influencing Policy

Science as a human right

By: Sarion Bowers, Policy Lead at the Wellcome Sanger Institute
Date: 09.11.18

It’s not news that Brexit represents a threat to UK science. From the inability to attract international talent, to the loss of funding and the problems getting imports into the country and exports out, UK science is in danger. Loss of science in the UK is not the loss of a luxury item. It is not a vanity project we can live without. UK science underpins the economy, from development of clean energy to the coordination of international clinical trials, the UK leads and we in the UK benefit. Failure to support UK science will leave all of us materially poorer. It will leave us with a less innovative health care system, with dirty air, and expensive food.

And after all of that we may also be deprived of a fundamental human right.

World Science Day

Tomorrow (10 November) is World Science Day for Peace and Development, a day to highlight the importance of science in and for society. This year’s theme is “Science, a Human Right”, in celebration of the 70th anniversary of the Universal Declaration of Human Rights.

The Universal Declaration of Human Rights

70 years ago, on Dec 10 1948, the Universal Declaration of Human Rights was approved by the United Nations. This Declaration laid out a manifesto of fundamental rights for all persons, of all nations. The Declaration is binding for all United Nations Member states, but many of the basic rights and dignities to be afforded to every person have since found their way into national and international laws around the world. For many people these rights fundamentally underpin their political outlook, whether left or right.

Despite near universal awareness of the existence of the Universal Declaration of Human Rights, many people probably do not know what all the rights are, or how far they extend into their society.

The first article of the Declaration states:

All human beings are born free and equal in dignity and rights. They are endowed with reason and conscience and should act towards one another in a spirit of brotherhood.

This is probably what most people think of when they think the Declaration of Human Rights. As we go through the articles, they move on to equality (Article 2) liberty (A.3) and prohibition of slavery (A.4), and torture (5). So far these are all reflected in the statement made in Article 1. But from here on the articles start to cover legal rights, privacy, movement, asylum and property rights. Reading the Declaration of Human Rights, the breadth of the rights are surprising and it is thought-provoking to imagine how the world might be were we to live by the vision laid out.

Science is a Human Right

Of all the articles, arguably the most surprising right comes in Article 27. It is laid out in two parts and states:

1) Everyone has the right freely to participate in the cultural life of the community, to enjoy the arts and to share in scientific advancement and its benefits.

2) Everyone has the right to the protection of the moral and material interests resulting from any scientific, literary or artistic production of which he is the author.

The idea that we all have a right to benefit from scientific advancement is something we do not often explicitly think about as a society. Public engagement practitioners recognise that people’s lives are improved when they understand and can engage with science but Article 27 is a different beast from public engagement. Article 27 does not say an individual has the right to learn about science so that they may make better choices for themselves. Article 27 recognises that science is a societal good and firmly makes the case that every individual has the right to benefit, regardless of their education, wealth or background.

Science in the UK

Science is a major player in the UK and we have all been benefiting from scientific advances. This benefit is not only from adoption of new developments but comes also from the wealth created by the fact the UK is a leader in many science and technology sectors.  From particle physics to genomics, the UK takes a leading role. The 100,000 Genomes Project has been ground-breaking in its efforts to bring genomics into the clinic. We host the European headquarters of many pharmaceutical, engineering and technology companies. We receive the largest share of European Research Council money behind Germany and we punch above our weight on publications and other research outputs.

Science from the most abstract academic project to commercial R&D is supporting the UK’s health and wealth.

About the Author

Sarion Bowers is the Policy Lead at the Wellcome Sanger Institute

Links:

Sarion Bowers’ profile on the Wellcome Sanger Institute website

How the Sanger Institute engages on scientific policy

Universal Declaration of Human Rights

World Science Day for Peace and Development 2018

The Darwin Tree of Life Project and the Earth BioGenome Project are aiming to sequence all animals, birds, fish, insects and plants in the UK and on earth, respectively
25 GenomesSanger Science

Sequencing All Life On Earth – Facts and Figures

Today (1 November 2018) a number of research organisations and funders announced the official launch of the Earth BioGenome Project – which aims to read the genomes of every species of animal, bird, fish, fungus, insect and plant on the planet. To help in this endeavour, the Wellcome Sanger Institute announced its intention to collaborate with a number of UK organisations to run the Darwin Tree of Life Project to sequence the DNA of all such life in the UK.

Below are 10 top facts that help to put the work into perspective…

 1. Let’s run the numbers

There are currently around 1.5 million catalogued eukaryote species on earth – that’s the known animals, plants, protozoa and fungi. But for a true total, estimates vary from 10-15 million species[1],[2]. There are an estimated 66,000 eukaryote species in the UK.

eurakyotes

2. Ages of extinction – we’re up to 6…

The planet is in the sixth great age of extinction[3]. The Living Planet Index reported a 60 per cent decline in vertebrate populations since 1970[4]. By the year 2050, up to 50 per cent of all existing species may become extinct, mainly due to human activity[3].

3. It won’t be cheap, but it will cost less than the very first human genome

To sequence an average vertebrate-sized genome costs about US $1,000. To sequence the genomes of all 1.5 million known eukaryotes, plus up to 100,000 new eukaryotic species will cost US $4.7 billion. This is less than the cost of creating the first draft human genome sequence (US $5 billion in today’s money). The timescales are equally comparable – the first human genome took 13 years to sequence; scientists aim to sequence all eukaryotes on Earth in the next 10 years.

4. Beetle mania

There are believed to be approximately 1-1.5 milllion different species of beetles

There are believed to be approximately 1-1.5 milllion different species of beetles

There are 400,000 identified species of beetles (Coleoptera) in 30,000 genera across 176 families. This represents about 25 per cent of all classified eukaryotic life. There are a predicted 1.5 million beetle species inhabiting the planet[5].

There is a story, possibly apocryphal, of the distinguished British biologist, J.B.S. Haldane, who found himself in the company of a group of theologians. On being asked what one could conclude as to the nature of the Creator from a study of his creation, Haldane is said to have answered, “An inordinate fondness for beetles.”[6]

5. There’s a long way to go…

There are fewer than 3,500 eukaryotic species with sequenced genomes. This represents less than 0.2 per cent of known eukaryotes.

scale

6. Botanical gardens of the world unite

Botanic gardens - such as Darwin Tree of Life Project partner Kew Gardens - contain approx 1/3rd of all plant life on earth

Botanic gardens – such as Kew Gardens – contain approx 1/3rd of all plant life

The collections of the botanical gardens of the world contain about a third of all species of plants, and more than 40 per cent of all endangered plant species[7].

7. It’ll take more than few usb sticks

The Wellcome Sanger Institute has the largest biosciences data centre in Europe, capable of storing and processing genomes of all sizes and complexities

The Sanger has the largest biosciences data centre in Europe, able to store and process genomes of all sizes and complexities

Storage and distribution of reference genomes and analyses will likely require less than 10 gigabytes per species or about 20 petabytes in total, well within current capabilities.[8] Storage of the underlying sequence read data for the completed Earth Biogenome Project is estimated to be approximately 200 petabytes. Total project information is likely to exceed an Exabyte of data.

8. DNA samples like it cold… very cold

DNA samples need to be stored at -80C

DNA samples need to be stored at -80C

For genome sequencing, ideally, DNA samples are frozen immediately upon collection. For long term storage, samples need to be kept at -80OC This isn’t always possible as resources may be limited at remote sites. Shipping samples over long distances can cause loss of DNA quality e.g. by thawing or leaking of preservation liquid. National networks of freezers, like the CryoArk BioBank will be used to store samples.

9. The world of fungi matters

Don't dismiss fungi - there are nearly 2-3.3 million different species, and they are vital for healthy ecosystems

Don’t dismiss fungi – there are nearly 2-3.3 million different species, and they are vital for healthy ecosystems

Fungi form one of the largest eukaryotic kingdoms, with an estimated 2.3-3 million species. They form a diverse group with a wide variety of life cycles, including mutualism[9] and parasitism. They have a broad and profound impact on the Earth’s ecosystem.[10]

10. There are three domains of life on Earth

How life is divided up - the three classes of life explained

The three domains of life

Life is categorised in to three domains:

  • Bacteria
  • Archaea
  • Eukaryota.

A domain is further divided into kingdom, phylum, class, order, family, genus, species.

Links:

News story: Genetic code of 66,000 UK species to be sequenced

News story: Launch of global effort to read genetic code of all complex life on earth


References

[1] Brendan B. Larsen et al, “Inordinate Fondness Multiplied and Redistributed: the Number of Species on Earth and the New Pie of Life,” The Quarterly Review of Biology 92, no. 3 (September 2017): 229-265.

[2] Hinchliff CE, et al. (2015) Synthesis of phylogeny and taxonomy into a comprehensive tree of life. Proc Natl Acad Sci USA 112:12764–12769.

[3]     Ceballos G, Ehrlich PR, Dirzo R (2017) Biological annihilation via the ongoing sixth mass extinction signaled by vertebrate population losses and declines. Proc Natl Acad Sci USA 114:E6089–E6096. AND International Union for Conservation of Nature (2017) IUCN 2016: International Union for Conservation of Nature annual report 2016 (International Union for Conservation of Nature, Gland, Switzerland).

[4] https://www.wwf.org.uk/updates/living-planet-report-2018

[5] http://www.pnas.org/content/112/24/7519?ijkey=09ba717ae0cbbc6bb750bedacf9b7db6e7b7969a&keytype2=tf_ipsecsha

[6] 1959 May-June, The American Naturalist, “Homage to Santa Rosalia or Why Are There So Many Kinds of Animals?” by G. E. Hutchinson, Page 146, Volume XCIII, Number 870.  [Taken from – 1959 May-June, The American Naturalist, “Homage to Santa Rosalia or Why Are There So Many Kinds of Animals?” by G. E. Hutchinson, Page 146, Volume XCIII, Number 870 (via Wikipedia.)]

[7] https://www.nature.com/articles/s41477-017-0019-3

[8] One Petabyte is 10×15 bytes. One petabyte is equivalent to 13.3 years of HDTV content

[9] Mututalism is where two organisms of different species exist in a relationship in which each individual fitness benefits from the activity of the other.

[10] http://www.pnas.org/content/pnas/114/35/9391.full.pdf

The Darwin Tree of Life Project and the Earth BioGenome Project are aiming to sequence all animals, birds, fish, insects and plants in the UK and on earth, respectively
25 GenomesSanger Science

The quest to sequence all life

Today (1 November 2018) the Earth BioGenome Project – a mission to sequence the genomes of all life on earth – was launched to the world’s media.

Unimaginable secrets are hidden in the genomes of the known, and unknown, species on our planet. The Sanger Institute is taking a leading role in this historic undertaking, as we plan to sequence the genomes of all 66,000 eukaryotic species in the UK.

Associate Director of the Sanger Institute, Dr Julia Wilson, talks about the ambitions, scale and challenges of this remarkable endeavour.

What is the Earth BioGenome Project?

EarthBioGenomeThe Earth BioGenome Project is a global collaboration, which aims to sequence the genomes of all eukaryote species on earth in the next 10 years. The ambition is vast. The project will transform science. We can only begin to imagine the benefits for advancing research into conservation, evolution, agriculture, biology and medicine.

Why sequence all life on Earth?

How life is divided up
Bacteria – such as MRSA and E. coli – relatively simple lifeforms which are single cells that have no membrane around their nucleus
Archaea – equally simple single cell lifeforms that are seen as the the oldest species of organisms on earth, and tend to be found in extreme environments
Eukaryota – everything else! These organisms have a nucleus with a membrane, and include animals, birds, fish, fungi and insects

All cellular life descended from a common ancestor, and genome sequences are the products of billions of years of evolution. Knowing the DNA sequences of all species will provide fundamental, transformative insights into biology.

There are an estimated 10–15 million eukaryotic species, and trillions of bacterial and archaeal species on Earth. But only a fraction of those – about 2.3 million, are actually known. We are only just beginning to understand the full splendour of life.

So far about 15,000 species, mostly microbes, have completed or partially sequenced genomes. From this, a wealth of knowledge has emerged, enabling enormous advances in agriculture, medicine, and biology-based industries and enhanced approaches for conservation.

Yet the world’s biodiversity remains largely uncharacterized. And the Earth has entered a period of unprecedented change. A new epoch – the Anthropocene – has been defined by human impact on the Earth’s geology and ecosystems. Human activity is threatening biodiversity through climate change, habitat destruction and species exploitation.

How life is divided up - the three classes of life explained

The three categories of life

We have a responsibility to care for our increasingly compromised planet. The project will produce a complete inventory of all life on Earth, and their complete DNA sequences; transforming our ability to monitor life as part of global conservation efforts.

It is essentially a mission to acquire knowledge of the natural world. That knowledge will form a foundation for future biotechnology.

Why now?

The family tree of life of life on earth. Ancestral tree courtesy of the Earth BioGenome Project

The family tree of life of life on earth. Ancestral tree courtesy of the Earth BioGenome Project

For the first time in history it is possible to efficiently sequence the genomes of all known species. In particular, the recent advances in DNA sequencing technology and the arrival of long sequence reads, mean that the project is now feasible.

A number of projects to sequence species for the first time are ongoing around the world. These include initiatives to sequence all birds, insects or bats. They are invaluable, but understandably fragmented and often shaped by funding limitations. Now is the time to bring everyone together, to co-ordinate DNA sequencing efforts. Joining these projects together will ensure consistency and deliver the best possible resource for future research.

How will this help with research into evolution, conservation, bio-diversity and health?

There are a broad set of scientific aims and outcomes of the EBP. The first is to revise and reinvigorate our understanding of biology, ecosystems, and evolution. This includes understanding the evolutionary relationships between all life on Earth, discovering new species, and uncovering fundamental laws that describe and drive evolution.

The second is to enable the conservation, protection, and regeneration of biodiversity. This includes clarifying how climate change and human activity are affecting biodiversity.

Finally, the goal is to explore the potential benefits for society and human wellbeing. This encompasses discovery of new medicines, enhanced control of pandemics, identifying new ways to improve agriculture, discovering new biomaterials, energy sources and biochemicals.

What role will the Sanger Institute play?

Organisations working together to read the genomes of UK fish, birds, animals, insects and plants

Organisations working together to read the genomes of UK fish, birds, animals, insects and plants

The Darwin Tree of Life Project will be an inclusive consortium of UK scientists and organisations. Key organisations are: the Sanger Institute, the Natural History Museum; Royal Botanic Gardens, Kew; EMBL-EBI; Earlham Institute; Edinburgh Genomics. Other institutes and organisations are expected to join. Together we will work to sequence all eukaryotic species in the UK, estimated at around 66,000 species.

We will also work with other countries to develop the global strategy for the EBP, and help to ensure that the benefits are shared.

What are the main challenges you can foresee?

Sample collection is a big challenge. It may be that we need to develop new machines or drones that can travel to hard to reach areas, for example sea beds. It’s possible they could be developed to extract DNA and store samples too.

The Wellcome Sanger Institute has the largest biosciences data centre in Europe, capable of storing and processing genomes of all sizes and complexities

The Wellcome Sanger Institute has the largest biosciences data centre in Europe, capable of storing and processing genomes of all sizes and complexities

Computing will also be a challenge. Requirements for data storage and processing are large – but tractable. In terms of computing power needed, mammalian-sized long-read genome assemblies currently require about 100 processor-weeks. The later phases of the EBP will require about 10,000 simultaneous assemblies running in parallel—a scale already approached by academic supercomputing centres.

Current tools are already capable of completing the project. But there is no doubt that genome assembly, alignment, and annotation algorithms will all need to be improved. It is a huge opportunity to develop new computational methods to maximize our understanding and use of the vast volumes of data that the project will produce.

How will you find all the species in the UK?

Finding, extracting and storing samples of all eukaryotic life in the UK is no easy task, and the Sanger will be working closely with the Natural History Museum, the Royal Botanic Gardens, Kew and other biobank repositories to fulfil the Darwin Tree of Life project

Finding, extracting and storing samples of all eukaryotic life in the UK is no easy task, and the Sanger will be working closely with a number of biobank repositories

For the Darwin Tree of Life Project, we’ll be working with UK organisations that have existing, extensive sample collections – including Royal Botanic Gardens, Kew; the Natural History Museum; the Culture Collection of Algae and Protozoa and others.

New sample collection will be required too. We’ll establish a dedicated team and strategy to survey the UK – gathering samples with the quality of DNA as their primary consideration. In the Darwin Tree of Life Project, we’ll be sequencing all eukaryotes in the UK. We won’t be sequencing non-native species, for example those in UK zoos.

Efforts to sequence all bacteria and archaea are already underway, so the EBP won’t be sequencing those.

Where will you start?

How species fit into the order of life. An animal such as a red fox would be in the domain of Eukaryota, in the Canidae family and the species Vulpes vulpes

How species fit into the order of life. An animal such as a red fox would be in the domain of Eukaryota, in the Canidae family and the species Vulpes vulpes

We have three starting points. Firstly, we will sequence a representative of each of the 3,849 families of species in the UK, plus a selected subset of species of particular interest.

Second, we will sequence all eukaryotic organisms from one or more ecosystems (e.g. St Kilda, Priests Pot or Wytham Woods).

Third, we will sequence all organisms from one or more of clades in the British Isles (group of organisms that consists of a common ancestor and all its descendants e.g. vertebrates).

How much is it going to cost?

The current estimate, for the whole EBP, is that sequencing all eukaryotic species will cost about $4.7 billion. This cost covers sample collection, sequencing machines, data storage, analysis, visualization and dissemination, and project management. Incredibly, this cost is similar to the cost of sequencing the first human genome, which in today’s money was about $5 billion.

The Darwin Tree of Life project is estimated to cost approximately £100 million over the first five years.

Will the sequences be made public?

Yes. UK species data will be publicly released and freely available via a dedicated website. EMBL-EBI will aggregate, curate and distribute assembly and gene sequences to the scientific community via a range of services and tools including Ensembl.

The data from the whole EBP will become a permanent foundation for future scientific discovery. The project will be working within international legislations to ensure that all countries can benefit from their involvement.  The EBP aims to provide fair and equitable access to genome sequence data and benefits it will bring.

Links:

News story: Genetic code of 66,000 UK species to be sequenced

News story: Launch of global effort to read genetic code of all complex life on earth

Long live bats
25 GenomesSanger Science

Long live bats

By: Alison Cranage
Date: 29.10.18


The golden flying fox is the largest bat known

The golden flying fox is the largest bat known

Bats hold an exclusive place in our collective consciousness – as creatures of the night, of vampires and witchcraft. They are truly unique mammals, essential to our ecosystems, with much to teach us about human health and longevity.

One in every five living mammals is a bat. There are over 1,300 species, spread across the globe in a wide range of ecological niches. The largest bat is the giant golden-crowned flying fox, weighing 1.6kg with an impressive 1.7m wing span.

Near the other end of the scale is the common pipistrelle bat (Pipistrellus pipstrellus) – the UK’s most abundant species. It weighs just 5g, or the same as a 20 pence piece. If you see a bat darting through the twilight it is likely to be a pipistrelle hunting down moths.

The common pipistrelle bat is one of the smallest bats known and easily fits in the palm of your hand

The common pipistrelle bat is one of the smallest bats known and easily fits in the palm of your hand

Emma Teeling is Professor at University College Dublin and Founding Director of the Centre for Irish Bat Research. World renown expert, she is our collaborator on the pipistrelle bat genome, which we sequenced as part of our 25 Genomes Project.

She is studying the whole range of exceptional adaptations of the bat. They are the only mammals which can fly, and use laryngeal echolocate. They also possess vocal learning, a rare feature among mammals.  Her most recent studies are into their unusual longevity.

A healthy life

The relationship between mammal size and lifespan is, on the whole, linear. Smaller mammals, with faster metabolisms, tend to have shorter lives. But some bat species live up to 10 times longer than would be predicted by their size. Not only do they live long lives, they live healthy ones. They can harbour a range of usually deadly viruses, including Ebola, SARS and rabies, yet they don’t get ill. Studying their immune systems could reveal new ways to treat these infections in people.

Bats are resistant to cancer too. In humans, the risk of developing cancer increases with age. Almost 9 in 10 cancer cases in the UK are in people aged 50 or over. Many other mammals also get cancer, but it is extremely rare amongst bats, naked mole rats, grey squirrels and elephants.

Secrets of the bat genome

The Myotis myotis species of bat is one of the longest lived, with some known to live to the ripe age of 42 years old. Image credit: Gilles San Martin, Wikimedia Commons

The Myotis myotis species of bat is one of the longest lived, with some known to live to the ripe age of 42 years old. Image credit: Gilles San Martin, Wikimedia Commons

Professor Teeling is combining a longitudinal study of one of the longest lived bat species with genomic and molecular analysis, to understand how bats age so healthily.

Her team visit Northern France every year to monitor a colony of about 700 Myotis bats – one of the longest lived species. Each member of the colony is tagged, and caught each year. A minute wing punch is taken and stored for later analysis, before the bat is released. One bat, first caught as an adult, has been caught again 42 years on, still healthy. The blood samples from the bats are used to study their genomes, cellular and gene function and immune system.

This enables the researchers to answer questions about the bat genome. Do they have the same age-related genes as other mammals? Do they regulate them differently? Or is there something else going on? Her work has already uncovered that genes involved in repairing the age-related damage at the ends of chromosomes may hold the key to bat longevity.

The pipistrelle bat lives five years on average. Comparing its genome to the longest lived species, like Myotis, will enable further discoveries.

Small genome

Bat Facts
Bats pollinate the flowers of the agave plant – essential to making tequila
In 1999 the soprano pipistrelle was formally identified as a separate species from the common pipistrelle, based on differing echolocation signatures
Male bats sing to attract females
A pipistrelle can eat 3,000 insects in one evening

Bats have the smallest genomes of all mammals. This could be an adaptation related to flight, as birds also have small genomes, but this is far from certain. Bats have highly active transposable elements in their genomes – these sequences of DNA copy and paste themselves, moving around the genome. In other mammals this leads to genomes growing over time as the copies stay – but bats must have a mechanism to remove them, because their genome has remained small. Studying bat genomes will help us understand this structural evolution, and uncover what is the minimal genome required to make a mammal.

1,000 Bats

Bat1K - 1000 bat genomes project

Bat1K – 1000 bat genomes project

Professor Teeling has set up the bat1k project – an effort to sequence the genomes of 1,000 different bat species. The sequence of the pipistrelle bat is just the start.

Usually out of sight, we perhaps don’t think about bats often. The pipistrelle is an iconic UK species, and highly adapted to live among us. The genome sequence will help researchers understand the native forna of the British Isles, as well as uncover the genetic basis of their unique features.

About the author:

Alison Cranage is a science writer for the Wellcome Sanger Institute.

Links:

The 25 Genomes Project

Bat1K Project

Sanger Science

Solving the mysteries of developmental disorders: The DDD study

By: Alison Cranage
Date: 16.10.18


Alix and Pip enjoying a day out. The genetic change responsible for their rare disease - DDX3X - was identified by the Deciphering Developmental Disorders team who read their DNA codes (and those of their parents) and compared them with thousands of other children and parents. Photograph used with kind permission of Clare Millington

Alix and Pip enjoying a day out. Photograph used with kind permission of Clare Millington

A rare disease is one that affects less than 0.5 per cent of the population. There are about 7,000 known rare diseases and on average, five new ones are described in the literature every week. Most are genetic, caused by mutations in a person’s DNA.

Some of the conditions may be familiar, like Huntingdon’s disease or cystic fibrosis, which affect thousands in the UK. Others affect just a handful of people in the world.

Clare Millington is mum to identical twins Pip and Alix, who have an extremely rare condition. They have difficulties with communication, sensory integration and movement. Alix also has type-1 diabetes. When they were younger, most of the girls’ hospital appointments were focussed on helping them with their symptoms.

Clare talked to us about her experiences.

“I was a little uncertain to start with when people started talking about learning difficulties whether that was a diagnosis in itself. It wasn’t really clear that wasn’t a diagnosis, it was just what manifested.”

The girls were 10 when their paediatrician in Newcastle suggested they join the Deciphering Developmental Disorders (DDD) study – to see if a genetic cause of their difficulties could be identified. They signed up and saliva samples were sent away for DNA analysis. Clare was busy, working and looking after the twins, and didn’t think more about the study until a letter came through the post four years later.

“We were told they had a DDX3X mutation and were handed a learned paper, which had been published just a month before. It was quite amazing to think they had found what had caused most of the girls’ difficulties.”

The diagnosis has had a huge impact on Clare’s family. They contacted the newly formed DDX3X foundation in America, and have connected with other families with the condition in the UK. Clare described how meeting others has been an amazingly positive experience.

“Previously we were on the sidelines. We’ve belonged to some cerebral palsy groups but we don’t quite fit. We’ve belonged to some communication aid users groups, but again, we’re the odd ones out. We were always welcomed but they weren’t like the other children.

“To have a support group of parents that totally identify with you is huge. You may not see each other or talk to each other often, but you do belong.”

There are now a total of just 250 girls in the world identified as having DDX3X Syndrome, though researchers think there are likely to be more. It’s clear that the condition is a spectrum, with some much more severely affected than others. But there are similarities between the girls too – and knowing about those can help with treatments.

“A lot of the girls have cortical visual impairment – their visual acuity is good, but actually the processing of the visual information is so poor that they are visually impaired.

“That’s very hard to pick up in a child with learning difficulties, because doing a sight test is tough. But once you know that it’s a common part of the condition, you can look for it. And think, maybe that’s the root reason they’re not learning to read or recognise shapes.”

Another common issue is constipation, which affected the twins too. At first, their inability to get potty trained was put down to their learning difficulties. But once people realised that there may be an underlying structural problem they looked further. It was found they have virtually no gut transit – this means the muscles in the gut aren’t working to move food along. Their treatment was changed.

“Knowing this helps them have a healthy life. Now we’re getting a treatment that actually works – because we know what the problem is. There is more research all the time, leading towards ways of getting good treatments.”

“I really think that the twins would be very much side-lined without their diagnosis. I really don’t think we would have moved forwards on many of the issues that they have without a diagnosis.”

Diagnosing thousands

In Numbers: Eight years of the Deciphering Developmental Disorders (DDD) Project

In Numbers: Eight years of the Deciphering Developmental Disorders (DDD) Project

Pip and Alix are two of over 13,600 children who joined the DDD study, which started eight years ago. Researchers at the Sanger Institute have been working with NHS clinical genetics services across the UK to identify, catalogue and analyse gene changes that may be responsible for a whole range of developmental disorders. None of the participants had a diagnosis before they joined the study.

Now, all the participants’ data have been analysed and reports are being passed back to their clinical geneticists. The DDD team have found diagnoses for about a third of the children. They are committed to re-analysing the data to try to find a diagnosis for as many of them as possible.

Dr Helen Firth, Consultant Clinical Geneticist at Cambridge University Hospitals Trust, and Honorary Faculty at the Sanger Institute, is one of the founders of the study. She described how new knowledge means they can continue to make new diagnoses.

“We’ve been re-analysing at regular intervals through the project. On our first thousand patients we achieved a diagnostic rate of 27 per cent. Three years later when we re-analysed the same data, with new knowledge, we can lift that diagnosis rate to 40 per cent. That’s based on genes we’ve discovered, and based on genes others have discovered and putting those into the mix. Plus, there are new tweaks to the pipeline – things that we’ve learnt to improve; the way we are filtering the data.”

The team expect the pattern to continue as the project runs until 2021.

Navigating the new ethical questions

The DDD ethics team used an online survey to gather people's views from around the world

The DDD ethics team used an online survey to gather people’s views from around the world

The study was one of the first of its kind in the world, looking at whole exome sequences of participants. It raised ethical issues, which were carefully considered from the outset, with the help of Professor Michael Parker and Dr Anna Middleton.

One of those questions was around ‘incidental’ findings. These are findings not related to the developmental disorder, and not looked for, but they could be important to the participant. For example, a mutation that increases the risk of developing cancer could be identified in someone’s DNA sequence. After careful consideration and consultation, the DDD team decided not to return these findings, should there be any, but to explore what kind of information people would want from such genome sequencing.

The DDD ethics team gathered the views from ~7,000 people from 75 different countries. They found that most people are interested in receiving genomic data, though not at all costs, particularly if it potentially compromises the ability to conduct research.

Bringing together the views of the public, patients, participants, clinical geneticists and researchers has shaped the debate in the UK and internationally. It has also set a strong precedent for similar projects, as genome sequencing becomes more widely available.

The future

Diagnosis by the DDD Project has transformed the lives of Alix, Pip and their family by helping them to connect with other families with the same condition

Diagnosis by the DDD Project has transformed the lives of Alix, Pip and their family by helping them to connect with other families with the same condition. Photo kindly provided by Clare Millington

A diagnosis doesn’t always change anything practical, like it did for Pip and Alix, but it is still important. Many families talk of a relief of finding out the cause of a condition. The diagnostic odyssey and years of testing are over.

DDD has over 200 associated research studies. These groups and collaborators are investigating the data to understand more about the conditions and the genes that cause them. 125 research papers have been published so far. Mutations in hundreds genes have been identified and 49 new conditions described.

Helen reflected on the eight years of the study.

“We’ve had the great good fortune to have excellent support from clinicians, scientists and families within the NHS. To bring those people together with the world-class team of scientists at the Sanger Institute has driven the study. It’s exceeded expectations. We’re continuing to discover new things using this data.”

“It really is a gateway. Once you can find what the genetic basis of these conditions is, it unlocks a lot of opportunities going forward.”

The team continue to open up these opportunities so that they can help more children like Pip and Alix.

As we move into the next medical era, genomics will be a foundation stone for many. Enabling research into some of the rarest conditions in the world now, will bring new options in the clinic for the patients of the future.

With thanks to Clare Millington for sharing her story

About the author:

Alison Cranage is a science writer for the Wellcome Sanger Institute.

Links:

For support on living with a rare condition, contact Rare Disease UK

Recruitment for DDD has now ended. See their website to find out more about the study

Read more about the project’s eight years on the Sanger website: Milestone reached in major developmental disorders project

25 Genomes: The Common Starfish. Image credit: Ray Crundwell
25 GenomesSanger LifeSanger Science

25 Genomes: The Common Starfish

By: Alison Cranage
Date: 04.10.18


starfish_alex_cagan

The other-worldly, bright orange, 5 limbed creature is instantly recognisable. Paddling on a Cornish beach, or rockpooling on the Isle of Mull at low tide – it’s pretty likely you’ll come across one.

Lurking in the shallow waters of the UK and across the North Atlantic, the common starfish (Asterias rubens) is one of 1,500 starfish species in the world.

Asterias rubens was nominated by the scientific community and won a public vote to sequence the genome as part of our 25 genomes project. The common starfish falls into our ‘cryptic’ category of creatures. Cryptic, because their behaviour and many hidden talents are not well understood.

Hidden talents

Starfish sperm
The DNA we collected for Asterias rubens was from its sperm. Professor Elphick’s lab in central London is home to some 200 starfish where he collected the sample for us to sequence.

Possibly the most remarkable feature of starfish is their ability to re-generate limbs. If a starfish is attacked or is in danger, it can lose an arm in order to escape. It then grows a new one in its place. Nobody’s exactly sure how this works, but the key to finding out will be in its genome. Understanding the process would have huge implications for regenerative medicine.

The starfish genome could also help research into glue, including surgical adhesives that are used to heal wounds. Asterias rubens feasts on mussels and other molluscs. To get to the meat inside a mussel, it attaches its tube feet to the shell, by secreting a glue, and pulls it apart. Researchers are interested in that glue, and the genome sequence might reveal more about its production and structure.

Neuropeptides

Professor Maurice Elphick is working with us on the starfish genome. His research interests lie in neuropeptides. These tiny molecules act in the brain to control a whole range of processes including pain, reward, food intake, metabolism, reproduction, social behaviours, learning and memory.

Starfish don’t have a brain, but they are more closely related to humans than they are to most invertebrates. They do have neuropeptides – and his team have discovered many already. Several are involved in the unusual feeding behaviour of starfish.

To eat a mussel, once it’s forced open the shell, a starfish pushes its stomach out of its mouth. It partially digests its prey, takes up the resulting mussel ‘chowder’ and then retracts its stomach.

“I’m interested in understanding the evolution of neuropeptide systems, and also want to compare their functions and to find out what homologous molecules are doing in very different biological contexts.”
Maurice Elphick, Professor of Animal Physiology & Neuroscience, Queen Mary University of London.
One of the molecules they discovered triggers the stomach retraction. The equivalent molecule in humans clearly has a very different role. Professor Elphick explained: “Interestingly, we have also found that the neuropeptide behind the stomach retraction is evolutionarily related to a neuropeptide that regulates anxiety and arousal in humans.”

Professor Elphick explained how the genome sequence will enhance their ability to discover and study more neuropeptides. Because neuropeptides are tiny, the genes encoding them are not always easy to find. The team will study the genome in places where other species are known to have neuropeptide genes, to see if they can pinpoint an equivalent in the starfish (an approach known as synteny). This is only possible because we are using ‘long-read’ technology in the 25 genomes project – so the genomes will be the best possible quality, with few gaps.

The future

The starfish genome is now sequenced and the raw data available for any researcher to use. Over the coming months, our partners at EMBL-EBI will be assembling and annotating it, marking the position of genes and other features.

The finished genome will enable researchers to answer their own questions. About evolution, glue, neuropeptides or growing new arms.


About the author:

Alison Cranage is a science writer for the Wellcome Sanger Institute.

Links: