Tag: Sanger Science

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

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:

10 surprises from sequencing 25 new species
25 GenomesSanger LifeSanger Science

10 surprises from sequencing 25 new species

By: Alison Cranage
Date: 04.10.18


Sequencing human genomes is now routine at the Sanger Institute. Bacteria, yeast, worms, malaria, and other pathogens are also all regularly sequenced in their thousands. Our people are pretty well known for sequencing the human genome, but we’ve also contributed to the first sequencing of many others including the mouse, rat, zebrafish, pig and gorilla too.

The 25 genomes project is an entirely different beast. It’s posing some new, and frankly very odd, challenges. The diversity of the new species means we’ve had a steep learning curve. Here’s a peek at some of the weird and wonderful things we’ve discovered so far:


New Zealand flatworms will explode if you freeze them - not terribly helpful when trying to extract DNA from samples... Image Credit: S. Rae, Wikimedia Commons

New Zealand flatworms will explode if you freeze them – not terribly helpful when trying to extract DNA from samples… Image Credit: S. Rae, Wikimedia Commons

1. Don’t freeze flatworms

They explode.

You may well ask why we’d freeze them in the first place. But freezing samples, or in this case, whole worms, is standard practice to store them ready for DNA extraction.

Freezing New Zealand flatworms didn’t go so well though. The resulting sticky goop proved difficult to handle… and to get DNA from.


Is this the Oxford Ragwort you are looking for? The best way to know is take a picture and send it to an Oxford expert... Image credit: Rosser1954, Wikimedia Commons

Is this the Oxford Ragwort you are looking for? The best way to know is take a picture and send it to an Oxford expert… Image credit: Rosser1954, Wikimedia Commons

2. It’s good to get a second opinion when you’re identifying something

The Oxford ragwort was chosen to sequence in our flourishing category. We have ragwort growing here on campus, so we took a plant for sequencing.

But once we started, we soon realised it was not the ragwort we were looking for. The plant we had was hexaploid (it has 6 copies of its genome in every cell). The Oxford ragwort, which we were hoping to sequence, is diploid (it has 2 copies).

We sent a photo of the plant to an expert at Oxford University, who informed us we had the common ragwort.


There 300+ species of blackberry - and telling them apart can literally take years of observation. Image credit: Fir0002, Wikimedia Commons

There 300+ species of blackberry – and telling them apart can literally take years of observation. Image credit: Fir0002, Wikimedia Commons

3. There are over 300 species of blackberry in the UK

Yes, 300+.

They differ in a whole host of characteristics; sweetness, number of drooplets (the little blobs that make up the fruit), colour, size, thorns, flowers, lifecycle and more.

Finding the right one wasn’t easy, but we did sequence the correct one first time this time. Read more about the blackberry saga.


Fen Raft Spider - more popular than beavers, apparently. Image credit: Helen Smith, www.dolomedes.org.uk

Fen Raft Spider – more popular than beavers, apparently. Image credit: Helen Smith, www.dolomedes.org.uk

4. Fen raft spiders are more popular than beavers

In a public vote, the fen raft spider won out over the beaver to have its genome sequenced.

Both were contenders in the flourishing category of the project. Over 5,000 votes were cast in total, as part of “I’m A Scientist Get Me Out Of Here”.


Scottish Featherworts are a lonely bunch, they're all male and their female partners are almost half a world away. Image credit: David Freeman, RSPB

Scottish featherworts are a lonely bunch, they’re all male and their female partners are almost half a world away. Image credit: David Freeman, RSPB

5. All the featherworts in Scotland are male

Their potential partners are over 4,500 miles away in the Himalayas.

Botanists don’t know when the populations split, or how they got there. They only reproduce clonally in Scotland, and so it is uncertain how long they can last in this way.


Bush crickets have issues #1 - their genomes are 2.5 times bigger than we expected. Image credit: Richard Bartz

Bush crickets have issues #1 – their genomes are 2.5 times bigger than we expected. Image credit: Richard Bartz

6. Genomes are not always what you expect

We estimated that the genome of the bush cricket would be 2Gb, about 2/3rds the size of the human genome. We were wrong.

The estimate was based on the average cricket genome from the animal size genome database. But in fact it is 2.5 times larger than the human genome, coming in at 8.5Gb.

Read more about how this affected the sequencing.


7. It’s good to share

We knew this already, but this project has been a huge collaborative effort. It wouldn’t have been possible without scientists giving their time and sharing their expertise.

The Natural History Museum are a key partner for the 25 genomes project. They are helping with species identification and collection, as well as providing a link to natural historians and species experts across the UK.

The sequencing itself wouldn’t have been possible without PacBio. They have provided a machine for the project and provided expert technical support to enable the sequencing of the new species.

Our other collaborators include EMBL-EBI, The National Trust, The Wildlife Trust, Royal Society for the Protection of Birds (RSPB), Nottingham Trent University, Edinburgh University, 10x Genomics, Illumina and many more. See the full list here.


Bush crickets have issues #2 - they have cannibal tendencies. Image credit: Richard Bartz

Bush crickets have issues #2 – they have cannibal tendencies. Image credit: Richard Bartz

8. Don’t put bush crickets in a box together

They eat each other (or parts of each other).


Scallops are 20 times more genetically diverse than humans. Image credit: Asbjorn Hansen

Scallops are 20 times more genetically diverse than humans. Image credit: Asbjorn Hansen

9. Scallops are more diverse than people

We’ve found that scallops have 20 times the diversity of humans.

The king scallop was sequenced in the dangerous category of creatures. Human genomes are just 0.1 per cent different to each other – that is, only 0.1 per cent of your DNA code is different to any other person on the planet.

We have a pretty good idea why human genomes are so similar. It’s likely that events in our evolutionary past, like ice ages or infectious diseases caused a genomic bottleneck, which meant only a small group survived.

In scallops, 1.7 per cent of the DNA differs between any given individuals.


Using Pacbio machines, we read 25 new genome sequences in less than 10 months. Image credit: Wellcome Sanger Institute, Genome Research Limited

Using Pacbio machines, we read 25 new genome sequences in less than 10 months. Image credit: Wellcome Sanger Institute, Genome Research Limited

10. We can go faster than we thought

This project started in January 2018. We’re barely into October.

We’ve sequenced 25 new genomes in less than 10 months.

The PacBio machines we are using have doubled the amount of data they produce, per run, in the last 12 months. Next year, they will quadruple capacity.


About the author:

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

Links:

25 GenomesHuman Cell AtlasInfluencing PolicySanger LifeSanger Science

25 years of pushing the scientific boundaries

By: Alison Cranage
Date: 01.10.18


Wellcome_Sanger_Logo_Portrait_Digital_RGBThe Sanger Institute was set up to uncover the code of life – the human genome. We opened our doors 25 years ago and became the largest single contributor to the human genome project. The principles that sat behind those endeavours are still fundamental – tackling the biggest challenges, openness and collaboration. Those principles have also helped to make Sanger one of the world’s leaders in genomics and biodata.

The Human Genome Project transformed science. The seemingly simple order of four letters of DNA changes how we understand life. Vast new areas of research have opened up, impacting biology, medicine, agriculture, the environment, businesses and governments.

Alongside our sequencing facilities, our activities and research have grown to utilise genomic knowledge. Now we are using genomics to give us an unprecedented understanding of human health, disease and life on earth.


hgp_300

Read our original press release from 2003 announcing the completion of the Human Genome by clicking on the image above

Sequencing at scale

From the completion of the first human genome in 2003, we moved to the 1,000 and 10,000 genomes projects. Being able to compare sequences between individuals enables the understanding of diversity, evolution and the genetic basis of disease.

One of our latest projects is to work with UK Biobank to sequence the genomes of 50,000 individuals. Participants have already provided a wealth of data about their health and their lives – from blood samples to details of their diet. Linking this information to sequence data means we can understand more than ever before about the connections between our genomes and our health.

Kamilah the gorilla. Image courtesy of San Diego Zoo. To read about our work with the gorilla genome, please click the image

Kamilah the gorilla. Image courtesy of San Diego Zoo. To read about our work with the gorilla genome, please click on the image above

Across a wide range of species

Sanger researchers also sequence the genomes of pathogens and other organisms, as well as people. We have published the genomes of thousands of species – from deadly bacteria to worms to the gorilla. This enables research into evolution, infections, drug resistance, outbreaks, symbiosis, biology and host parasite interactions.

sequencing_output

The cumulative amount of DNA the Sanger Institute has read over time

At increasing speed and accuracy

Our sequencing teams, led by Dr Cordelia Langford, are constantly developing the technology to improve both accuracy and speed. In early 2018, we celebrated sequencing over five petabases of DNA (if you typed it all out, it would take 23 million years). The first petabyte took just over five years to produce. The fifth, just 169 days. The amount of genomic data now rivals that of the biggest data sources in the world – YouTube, Twitter and astrophysics.

sanger_data_centre

We run the largest life sciences data centre in europe

Supported by Europe’s largest life sciences data centre

The Sanger Institute is not only developing sequencing technology but also leading research in computational science, IT and bioinformatics, developing new ways to store and analyse petabytes of genomic and bio-data.


From sequence to clinic

How genome sequencing, or the sequence of any given individual, can be used hasn’t always been clear. But in the case of rare genetic diseases, it can change lives.

ddd_logo

To read more about the Deciphering Developmental Disorders project, please click on the image above

Giving families an answer

The Deciphering Developmental Disorders (DDD) study started 8 years ago, led by Dr Matt Hurles at the Sanger Institute. Over 13,600 children with rare developmental conditions, but without a diagnosis, joined the study. Sanger researchers, working together with clinical geneticists, have used genome sequencing to diagnose their conditions. 40 per cent of the children now have a diagnosis – giving the families some of the answers they were searching for. Knowing the genetic cause of a condition can help doctors manage it, help families connect with others as well as plan for the future.

Watch our video about tracking MRSA in real time

Watch our video about tracking MRSA in real time by clicking on the image above

Stopping outbreaks in hospitals

The ability of researchers to rapidly sequence and analyse bacterial genomes is also leading to advances for patients.

Dr Julian Parkhill and colleagues showed it was possible to track an MRSA outbreak in a neonatal ward in real-time. By sequencing MRSA isolates from patients and staff, they could track the outbreak, following its path from person to person. This enables clinicians to prevent further transmission and bring the outbreak under control.

Now, it is UK policy to sequence the genomes of pathogens in an outbreak.

Watch our video showing global tracking of infectious disease

Watch our video showing global tracking of infectious disease by clicking on the image above

Fighting epidemics at a global scale

But disease knows no borders. Pathogens can easily spread around the globe. Professor David Aanensen, group leader at the Sanger Institute, is also Director of the recently established Centre for Genomic Pathogen Surveillance. The centre co-ordinates global surveillance of pathogens (such as MRSA and the flu virus) using whole genome sequencing. The data is openly available. Countries around the world can monitor the rise and spread of pathogens as well as their growing resistance to antibiotics. This enables swift action – with the aim of stopping transmission and saving lives.


The forefront of human genomics

The rapid development of technology has led to the ability of researchers to sequence the DNA, or RNA, from a single cell. Previously, much larger quantities of material were needed. Single cell RNA sequencing is a powerful tool. It allows the study of an individual cell’s activity, functions and composition. And high throughput machines means hundreds of thousands of cells can be analysed at once.

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To view the full infographic for the Human Cell Atlas project, please click on the image above

Capturing every type of cell in the human body, one at a time

The Human Cell Atlas is capitalising on these advances. The international collaboration is co-led by Dr Sarah Teichmann at the Sanger Institute. Launched in 2016, scientists are using Next-Generation Sequencing to sequence 30-100 million single cells from the human body – out of a total of roughly 37 trillion. The aim is to create a comprehensive, 3D reference map of all human cells. This will lead to a deeper understanding of cells as the building blocks of life. It will form a new basis for understanding human health and diagnosing, monitoring, and treating disease.

Like the human genome project before it, this huge project will disrupt science and human biology. And like the human genome project it will drive technology to make it possible.


The diversity of life

Beyond human health, genome sequence data allows the study of evolution, biology and biodiversity.

25logopng

To read more about our 25 Genomes Project, please click on the image above

25 Genomes for 25 years

For our 25th anniversary we have sequenced a more diverse range of species than ever before. 25 different species that represent biodiversity in the UK – from the golden eagle to the humble blackberry. Sequencing new species will push development of our technologies as each presents unique challenges. The sequences themselves will aid research into population genetics, evolution, biodiversity management, conservation and climate change.

But 25 species is just the beginning. Every single living thing has a genome, made up of exactly the same molecules of DNA or RNA. We want to uncover how the order of those molecules lead to the diversity of life on earth.

A_Novel_Representation_Of_The_Tree_Of_Life

To see the full sized tree of life diagram, please click on the image above

It took 13 years to sequence the first human genome. When the project began, no-one knew where it would lead. Now we sequence the equivalent of one gold-standard (30x) human genome in 24 minutes – faster and deeper genomic insights are enabling discoveries that improve health and our understanding of biology. These insights are happening right now, and they will lead to unimagined benefits for future generations – all possible from a sequence of four letters of DNA code.


About the author:

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

Links:

Mosquito in close up. Image credit: CDC/Dr Paul Howell
Sanger Science

Building capacity for genomic surveillance of malaria mosquitoes in Africa

By: Alistair Miles
Date: 21/09/2018

In 2009, a group of African entomologists and public health professionals founded the Pan-African Mosquito Control Association (PAMCA). The aim was to bring together mosquito control professionals from across the continent, and provide a platform to build capacity and coordinate efforts to improve mosquito control and prevent diseases like malaria. A few years later, in 2013, we began work at the Sanger Institute on a new project to sequence the genomes of more than 1,000 malaria mosquitoes collected from across Africa. It’s taken time for that work to bear fruit, but the project has now generated a wealth of new data that could be put to practical use.

Children sleeping under an insecticide-treated bednet. Photo credit: Martin Donnelly

Children sleeping under an insecticide-treated bednet. Photo credit: Martin Donnelly

Thanks to new funding from the Bill and Melinda Gates Foundation, these efforts are now coming together, and PAMCA has recently invited researchers to propose new projects on mosquito genomics in Africa. Our mosquito team at the Sanger institute is excited to be supporting those projects, and will sequence the whole genomes of thousands of new mosquitoes collected from locations where we currently have little or no data.

Mosquito-borne diseases, particularly malaria, still have a devastating impact on public health in Africa, and massive efforts are made each year to control mosquitoes. For example, in 2017 the Global Fund paid for 197 million insecticide-treated bednets to be distributed in Africa. This approach has led to major reductions in disease, but brute force can only get you so far. Under this intense and uniform pressure, mosquito populations are rapidly evolving, and insecticide resistance has spread across the continent. As we struggle now to gain the upper hand, those working at the front line of mosquito population monitoring and control have a pivotal role to play.

In an ideal world, every province in every malaria-endemic country would have a well-trained, well-resourced, dedicated team of medical entomologists. Those teams would regularly collect data on local mosquito populations and run experiments to compare different tools and tactics for mosquito control. They would assess whether current mosquito control efforts are still effective, give advice on the best plan of attack for the next season, and raise the alert about any changes in local mosquitoes, such as the emergence or spread of a new form of insecticide resistance.

In some parts of Africa, this vision is not so far from reality. But there is a broad consensus that much more could be done to build capacity for mosquito population monitoring and surveillance. With recent advances in genomics, there is also now an opportunity to equip teams with new tools to collect richer and more relevant data, and to join up data and coordinate efforts across countries. This is why the Gates Foundation and the Sanger Institute are partnering with PAMCA and supporting this new funding call.

Training session in sampling mosquito larvae for community volunteers. Photo credit: Prosper Chaki

Training session in sampling mosquito larvae for community volunteers. Photo credit: Prosper Chaki

The Sanger Institute has committed to provide genome sequencing for all of the new PAMCA projects. The call will fund nine projects in total, each lasting 12 months, and our aim is to sequence whole genomes of 500 mosquitoes from each project. A particular focus of this call is to fund projects working in locations where little or no data on mosquito populations has so far been collected. Ironically, these are often areas with high rates of malaria, and so filling in these gaps in our continental map of mosquito populations is vital.

Last year we published results from the largest ever genomic study of mosquitoes, which sequenced Anopheles gambiae mosquitoes, the species primarily responsible for transmitting malaria, collected from eight African countries. We found evidence that insecticide resistance is emerging locally in a number of geographically distinct mosquito populations, but it is also spreading between mosquito populations in different countries, in some cases separated by thousands of kilometres. These findings show that how insecticides are used in one location can have an impact on many other locations, and that mosquitoes, of course, do not respect political borders. The management of insecticide use, therefore, has to be coordinated.

Unlike the Aedes mosquitoes that transmit dengue and zika, which can travel over large distances by laying their eggs in car tyres, it is more likely that insecticide resistance spreads between Anopheles mosquito populations by adult mosquitoes flying to find new food and breeding grounds. But although we know that an insecticide resistance gene can find its way into populations as distant as Guinea and Angola, for example, we still don’t know where resistance is emerging, or what routes it can take as it spreads outwards from any given origin. Filling in these gaps in our understanding of mosquito movement and gene flow is a major goal of the new PAMCA projects.

Mosquito larvae. Photo credit: Martin Donnelly

Mosquito larvae. Photo credit: Martin Donnelly

Insecticides are likely to remain an essential component of mosquito control for the foreseeable future. But because of the challenges of resistance, and the significant costs and logistical issues involved in distributing millions of nets and spraying hundreds of thousands of homes each year, efforts are being made to develop alternative methods of mosquito control. New methods based on gene drive, where a selfish gene is introduced into a mosquito population and then spreads to cause the population to crash or become unable to transmit disease, have been proven to work in the lab, and are now being developed for use in the field. There are considerable technical, regulatory and logistical hurdles still to be overcome, but the technology has the potential to transform mosquito control in Africa. Understanding how mosquito populations are connected across Africa is obviously a prerequisite to planning any kind of deployment of gene drive, so sequencing mosquito genomes from across the complete geographical range of the species is all the more important.

Since its inception, PAMCA has established chapters in 8 countries, formed strategic partnerships with regional bodies and academic institutions, performed an Africa-wide assessment of entomological capacity, and run training workshops on gene drive. PAMCA has also held annual conferences in Kenya, Tanzania, Nigeria and Burkina Faso, bringing together entomologists, researchers, health professionals and members of governmental and non-governmental organisations. From 24-26 September, the 5th annual conference will be held in Victoria Falls, Zimbabwe. I’m excited to be attending the conference for the first time this year, and to be participating in a symposium on mosquito genomics, alongside colleagues from Sanger, the Liverpool School of Tropical Medicine, and PAMCA. It should be a great opportunity to discuss the new funding call. Hopefully the new PAMCA projects will go some way towards increasing capacity both for basic medical entomology and for the analysis and interpretation of genomic data, as well as generating a wealth of new data from contemporary mosquito populations in understudied locations.

Applying for PAMCA funding

Researchers interested in applying for the PAMCA funding, please see the PAMCA request for proposals document for more information. The closing date for the first round of applications is 3rd October.

About the author:

Alistair Miles is Head of Epidemiological Informatics in the group of Dominic Kwiatkowski, at the University of Oxford, and the Wellcome Trust Sanger Institute.

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