Category: Sanger Life

Living and working at the Sanger Institute

Getting a hold of some samples… for the 25 Genomes Project
25 GenomesSanger LifeSanger Science

Getting a hold of some samples…

By: Dan Mead, the 25th Anniversary Sequencing Project Coordinator
Date: 29/01/2018

[Because gathering samples is proving to be quite a major task, I’m going to split this across several posts]

First things first – find a sample

The first, and often most difficult, part of getting a sample for the 25 genomes project is finding out where from.

There are a number of reasons for this but it essentially boils down to the fact that the Sanger Institute has always focused¹ on human health and disease so we don’t have a particularly great list of contacts for this project.

¹There have been some dalliances into other areas in the past, notably; Cod, Coelocanth (it’s fish, known as a ‘living fossil’, although I prefer something that implies it’s been a long-term success like ’Pan-eon species’, a description I may have made up), Tasmanian Devil Cancer, Tomato and a butterfly

The ones that are most difficult to get are the ones that the steering group decided upon independently, this is because without a scientist/researcher/expert putting forward the species there isn’t anywhere to start from.

This is where working in science has a great advantage- collaboration. In the fields of Agricultural, Plant & Animal and Environment/Ecology sciences half of all articles were written by multiple institutions by 2009² and if the trend has continued it should be over 60% by now.

²Gazni, A., Sugimoto, C. R. and Didegah, F. (2012), Mapping world scientific collaboration: Authors, institutions, and countries. J. Am. Soc. Inf. Sci., 63: 323–335. doi: 10.1002/asi.21688

This is one reason why we need to collaborate more and will be subject of a later post.

How traditional biologists and computer biologists work together. #CartoonYourScience by @redpen/blackpen https://twitter.com/redpenblackpen

How traditional biologists and computer biologists work together. #CartoonYourScience by @redpen/blackpen https://twitter.com/redpenblackpen

(for more like this check out the wonderful @redpenblackpen)

In practice this should mean that us scientists are a helpful bunch, and it turns out this is true. Whereas cold-calling/emailing people about the ‘accident you’ve been recently involved in’ or ‘the security breach on you Microsoft device’ are extremely annoying [pro-tip, pass the phone to your pre-school child if this happens, the results are normally quite amusing] doing the same to a scientist to offer them free sequencing of their species of interest is generally quite warmly received!

Getting a Golden Eagle(‘s DNA)

So lets’ have a closer look at some of the species, firstly the Golden Eagle.

I would have thought that this would be a tricky one – they’re protected by a bunch of laws/regulations which means that without special licences you can’t mess with them. In fact even the locations of the nests are a closely guarded secret as they are still being illegally killed or the eggs are taken by collectors.

Turns out that a quick google and one email can lead to a great result, although it’s tinged with a bit of sadness which I’ll get to in a bit. I initially contacted Professor Anna Meredith at Edinburgh University with a general ‘can you help me with blah, blah, blah’ as she works with a number of species we were interested in (in this case I was actually after Red Squirrels) and she forwarded this on to Dr. Rob Ogden, also at Edinburgh.

As it turns out he is already working on Golden Eagles and was planning on doing some sequencing with some collaborators in Japan (they have eagles there too). Even better he had samples already from (here’s the sad bit) chicks that had died in the nest (plus one found rather suspiciously in a long abandoned nest).

So, one sample down, 24 to go!

[By the way I’m not going to go into the logistics and ENORMOUS cost of shipping things on dry ice, just assume that things arrive magically, but I may expand on why they need shipping this way some other time.]

Something squirreled away

Anna couldn’t help out with the Red Squirrel however, so I asked the National Trust who maintain a lot of the areas where these cute little critters still live:

UK Squirrel Distribution Maps, 1945 and 2010. Image Credit: Craig Shuttleworth, RSST

UK Squirrel Distribution Maps, 1945 and 2010. Image Credit: Craig Shuttleworth, RSST

A nice lady called Laura put me in touch with the Head of Conservation (David Bullock) who in turn linked me to Andrew Brockbank at Formby Point who then led me to Kat Fingland (Nottingham Trent University) and Rachel Cripps (Red Squirrel Officer). All this took about a month and a bit but I finally had the right people. Thankfully we didn’t need any extra licencing to get some samples as they were already collecting from animals that had died from natural or accidental causes.

2 down, 23 to go!

Ethical and responsible sampling

It’s worth mentioning at this point that for this project we want to limit the impact of our sampling as much as possible and therefore have had it approved by our AWERB (Animal Welfare and Ethical Review Body). What this means is that wherever possible we do not kill any animals solely for the project, although in practice this is easier said than done and it does create some difficulties.

  1. For some animals this is not a problem as they are large enough that we can take a small amount of blood (less than 1ml) but others are too small for this to be possible (pipistrelle bats for example weigh around 5g and have only 0.5ml blood in total). This means that we need to get hold of whole animals AND as some of our species are protected (Golden Eagle, Red Squirrel etc.) they need to have already passed away for us to be able to use them.
  2. Another related issue is that the protected species need special licences to take blood samples from even if they are large enough for this to be possible. Given the amount of time for the project it’s not really an option, so again we need naturally passed on animals.
  3. The nature of the sequencing technology we’re using means that we need to get really long bits of DNA (upwards of 150,000 base pairs – that’s the A-T/G-C parts of DNA). The problem is that when we use animals that have died of natural causes we need to find and sample them really quickly: as soon as the animal dies the DNA begins to break up through the natural decomposition process.
  4. The really small critters (invertebrates like the Roesel’s Cricket for example) are next to impossible to find when they’ve died, as they tend to be eaten by other things and are hard to spot unless they move. In these cases we have no choice but to take live creatures and euthanise them as humanely as possible.
  5. Plants and fungi are somewhere in the middle, we need quite a lot of material (DNA extraction is more difficult), but ethically it’s acceptable to take bigger samples, so in these cases we take cuttings or fruiting bodies.

So that’s it for this one, more on sample collection to come…

About the author:

Dan Mead is the 25th Anniversary Sequencing Project Coordinator, for the 25 Genomes Project for the Wellcome Sanger Institute, Cambridge.

More on the 25 Genomes Project:

25 Genomes Project web page 

Giant Hogweed - one of the 25 genomes being read by the Wellcome Sanger Institute. Image credit: Appaloosa, Wikimedia Commons
25 GenomesSanger LifeSanger Science

Giant Hogweed sampling, a retrospective

By: Dan Mead, the 25th Anniversary Sequencing Project Coordinator
Date: 14/12/2017

Anticipating that the Giant Hogweed would not win the popular vote in the “I’m a scientist, get me out of here – 25 Genomes…” event I decided to try to find some.

Let your fingers do the walking…

The National Biodiversity Network (NBN) atlas is incredibly useful for finding out where (and when) things are found, so I started there, looking for Heracleum mantegazzianum within 5km of the Sanger Institute:

Giant Hogweed locations in a 5km radius from the Wellcome Genome Campus

Giant Hogweed locations in a 5km radius from the Wellcome Genome Campus

This was a bust though, they’d been cleared out (the records are from 2004 and 2011 so no surprise there). So I went to a different source- the BSBI (Botanical Society of Britain and Ireland) who are linked to NBN but I figured would be more specific. I was right, you need to register to get the information but once you do, it is very good.

A nice chap called Kevin Walker sent me their records for the Cambridgeshire area. Turns out we’re in a bit of a hotspot, so that’s good news. Unfortunately by the time I found this out, it is November and plants tend to die back in the autumn.

On the other hand I had read somewhere that giant hogweed will germinate in winter so I figured that it might be possible to find some youngish plants – these are ideal for DNA as growing parts are the best for extraction.

It’s a matter of record

From the records I found out who had seen the plants in question and one of the most recent was a chap called Jonathan D. Shanklin who’d seen one in central Cambridge, on Hobson’s conduit. This, by the way, is a water channel cut approximately 400 hundred years ago as a water source for the centre of Cambridge and is now protected as a scheduled ancient monument.

Digression aside, with a name like that it was relatively easy to find Mr Shanklin with a quick google search. Turns out he works for the British Antarctic Survey. One slightly awkward phone conversation later I had clear idea of where this plant would be, not far from the Botanical Gardens. However driving in to the centre of Cambridge isn’t much fun, so this option went on the back burner.

Handle with care

Skin blistering caused by giant hogweed. Image credit: Cosima Pferdeliebe, Wikimedia Commons

Skin blistering caused by giant hogweed. Image credit: Cosima Pferdeliebe, Wikimedia Commons

Here’s a little tangent, this plant is not something to be trifled with. Giant hogweed is nasty stuff, its sap contains a sunlight (UV) activated toxin that can cause pretty horrible blistering (see below). So I made sure that I stocked up on a full face shield [liberated from a past position], plenty of nitrile gloves and a Tyvek suit (thanks to John Lovell at the Sanger).

The next location I wanted to scout out (I like to have backup plans) was the Bourne Brook area as this had a whole bunch of recorded sightings over the past few years (by a Ruth Hawksley) so I went for a little drive as it’s only 15 mins from work.

It turns out that Bourne Brook has been very effectively cleared of hogweed this year so I went to the workplace of Ruth Hawksley. Ruth works at the Bedfordshire and Cambridgeshire Wildlife Trust and they have an office that’s open to the public just 10 minutes from the brook. Sadly she wasn’t there.

However, her colleagues were in and they gave me her card. After a fruitful telephone chat, Ruth embarked on a mission to find some for me. This did not go well so we had an email exchange over the following days about getting hold of some seeds so that I could grow some myself. Again, no success as all the plants had been sprayed. Then Ruth remembered that there was a plant found and de-headed this past summer, rather handily just up the road from me in Ickleton, so off I went.

Lost in translation

Time for another aside. The location I was given was TL49384419 and a street. It seems that there are more ways to record location information than you might think. The above is an example of the Ordnance Survey National Grid coordinate system and it seems to be the standard for biological sample recordings in the UK.

Another nugget I discovered earlier in the project is that iPhones record GPS coordinates in the metadata of pictures. It isn’t easy to extract without using 3rd party software. However, if you do, you can then translate it from “AA; B; CC.cccccc” to “AA.B.CC.ccccc” which you can then copy and past into Google maps.

Anyhoo, a short walk up the lane later and I find myself standing by an electricity substation in Ickleton, looking somewhat suspicious in a pair of bright orange gloves, and staring at this:

Giant hogweed in the wild (hiding beside an electricity substation in Ickleton)

Giant hogweed in the wild (hiding beside an electricity substation in Ickleton)

This is the hogweed you’re looking for

One quick email later (thank you 4G connectivity) and Ruth confirms that this is the plant I’m looking for. Further confirmation came from around the back of the ‘station where there’s a 2m dead stem that’s been de-headed. So I took one of the leaves back to the lab to deposit in the -80 degree freezer, success!

About the author:

Dan Mead is the 25th Anniversary Sequencing Project Coordinator, for the 25 Genomes Project for the Wellcome Sanger Institute, Cambridge.

More on the 25 Genomes Project:

25 Genomes Project web page 

Sanger Life

Alzheimer’s Disease: The puzzle we’re so desperate to solve

By: Fiona Calvert
Date: 13.11.17

MaxP17_JonBarlow_Copyright-MRC_102017_fiona

MRC Chairman Donald Brydon CBE and Fiona Calvert at the MRC Max Perutz Science Writing Awards 2017.  Photo credit: MRC

This article was shortlisted for the MRC Max Perutz Science Writing Awards 2017.
“But Alzheimer’s is me, unwinding, losing trust in myself, a butt of my own jokes and on bad days capable of playing hunt the slipper by myself and losing. You can’t battle it, you can’t be a plucky “survivor”. It steals you from yourself.” – Terry Pratchett 2008.

Author Terry Pratchett, who was diagnosed with a form of Alzheimer’s disease in 2007, worked tirelessly until his death to beautifully articulate what living with dementia was like for him. Not just the memory loss, but also the loss of independence, personality, of your ability to maintain relationships and ultimately the loss of yourself. He gave people robbed of their memories, and themselves, a voice.

Dementia is estimated to affect 46.8 million people worldwide, with the number predicted to double every twenty years. In 2015 there were nearly 10 million new dementia cases, that’s one new diagnosis every three seconds. Alzheimer’s disease is the most prevalent form of dementia but it’s about more than just facts and figures: it’s about the people whose lives it steals.

Any diagnosis can be daunting for a patient, but a diagnosis coupled with no effective treatment, let alone a cure, is terrifying. Terry Pratchett used his voice in the best way, to fight for more exposure and to fight for a cure. As a scientific community it is our responsibility to take up that fight. In order for effective treatments to reach patients we have to understand the disease we’re fighting. My PhD will hopefully help to do just that.

At the Sanger Institute, where my PhD is based, we are fascinated by all things genetics, which may seem a long way from a patient suffering from Alzheimer’s disease. Yet we know that certain gene mutations (a small error in a gene) can increase your risk of getting Alzheimer’s disease and now we are working to understand how and why that is.

Creating a list of Alzheimer’s disease risk mutations is like having all the edge pieces of a puzzle put together – it doesn’t show us the full picture but it creates a guideline that makes filling in the middle a little bit easier. The puzzle of Alzheimer’s is huge and so, although the hope is that one day we will see the full picture, today, I’m looking at just one corner.

The edge I spend my days looking at, trying to understand how the puzzle pieces fit, is the part that involves your immune system. The same immune system that helps you fight off a cold plays a vital role in Alzheimer’s disease. We didn’t really know this until we found the edge pieces of our puzzle – that list of gene mutations that increase your risk of getting Alzheimer’s disease includes some that affect your immune system.

So we have the edge of our puzzle, but what next? I’m taking those small errors in genes and looking at how they affect your brain’s specialised immune system. This is where, for me, the science gets really cool and it’s the part of my day-to-day that reminds me why I am so fascinated by science.

Until recently, studying the brain’s immune system was nigh on impossible – these cells are not exactly accessible. However, we hope that a new form of stem cell, induced pluripotent stem cells, are going to change that. These cells are incredible: they have the potential to turn into any other cell in the body and all we need to create them is a tiny skin sample. Then with a bit of reprogramming (and a lot of patience), we can turn that sample into stem cells.

Stem-cells-to-Microglia

Microscope images of induced pluripotent stem cells (left) and (right) after 20 days of development into cells that are similar to microglia.

I’m taking these stem cells, that have the specific gene errors from our list, and turning them into microglia. Microglia are an integral part of your brain’s immune system. They act like scavengers, hunting for things that definitely don’t belong, ingesting and destroying them. Being able to make these cells in a lab means that we can finally understand their role in Alzheimer’s disease (something that is currently very unclear) and how those genes from our list can change their behaviour.

Sometimes my days are spent so focused on my small corner of the Alzheimer’s disease puzzle, it is easy to forget why we are doing this in the first place. Every day people across the world suffering from Alzheimer’s disease lose that little piece of their memory, that little piece of themselves.

I am proud to work on a small corner of this much larger puzzle, in the hope that one day soon we’ll be able to pull all our small corners together. I am proud to be part of the fight, the fight that gives patients hope that one day they may be “plucky survivors”.

About the Author:
Fiona Calvert is a PhD student at the Wellcome Trust Sanger Institute in the group of Daniel Gaffney.  She is studying the how genetic changes affect the brain’s immune response, focusing on developing a stem cell model for inflammation of neurons.

 

Links:

 

 

Sanger Life

In search of the hidden reservoir of Malaria

DATE:20/12/16
By Arthur Talman

On our third night in the village, we are woken up by the wail of a grieving father. His 3-year-old son has just succumbed to malaria during the night and he has come in desperation to seek help. This happened in a village where treatment was freely available and tragically reminds us that the fight against malaria requires societal and educational interventions as much as scientific and technical ones.

The next morning over a traditional fonio breakfast, faces are groggy and still carry the night’s tragedy. Our team, composed of 2 clinicians, 2 microscopists and myself in charge of entomology, is readying for our days’ work in Faladje, a small village in central Mali.

falaje-pic1

Faladje is a small village with a population of about 5,000 and lies in the southern central part of Mali. Most inhabitants live off agriculture of cotton, millet, mango, watermelons and livestock.

Humans are the sole reservoir of the deadliest malaria parasite Plasmodium falciparum, and it is this parasite that our research focuses on. These parasites can only infect new people after spending a couple of weeks inside a mosquito. This fact means that every new case of malaria originates from an infectious mosquito bite. In the Lawniczak Lab at the Sanger Institute where I am a postdoc, we are interested in the interactions between malaria parasites and vector mosquitoes. My project in particular is focused on how parasites behave inside of people to increase their chances of ending up inside of a mosquito, and thus eventually a new person.

There are several different “stages” of parasite that live inside the human red blood cells. The stages that cause fever and death are replicating inside of red blood cells, then bursting and infecting new red blood cells. Other stages, known as gametocytes, are waiting to be taken up by a mosquito where they will mate and develop over the next 10 days or so.  It is the gametocytes that are the focus of the project I’m here to carry out in Mali.

A paradox lies in the fact that some people can transmit parasites to mosquitoes even when none can be seen in their blood. We are researching whether gametocytes are at higher densities in the skin where mosquitoes actually get their bloodmeals from, than in the freely circulating blood. To do this, we compare gametocytes inside mosquitoes that have fed on blood naturally versus artificially. Natural feeding is the kind that is making you itchy right now…a mosquito lands on you, inserts her proboscis, and finds a capillary to puncture and drink from. Artificial feeding is where we take blood from the vein and feed it to mosquitoes through an artificial membrane, visible in the photo below.

bloodmeal

Mosquitos taking a bloodmeal on an artificial membrane feeder.

This work requires working with very tiny amounts of biological material. Although a mosquito can drink her weight in blood, it’s still a very small volume to work with (a blood meal is around 2 microliters). I have spent the better part of the last year at the Sanger Institute setting up molecular assays capable of detecting the sexual stage gametocytes and characterising their genetics with so little material.

rdt-test-pic

Malaria rapid diagnostic tests (RDT) on a random morning, the ones with two bands are positive.

Conducting this research poses some ethical questions. Although harmless, naïve mosquito bites are uncomfortable and sometimes painful. We have obtained ethical approval from an Internal Review Board and have conducted a comprehensive community consent procedure with local notaries in the village and set up some very strict inclusion criteria and individual consent procedures. The village will benefit from our presence for the time we are there, with free treatment for any disease and all included patients will be included in a comprehensive follow up for 28 days. On my first inclusion I am nevertheless nervous. I have conducted field work before but it is the first time I’m leading it and the first time we are feeding mosquitoes directly on children in this village.

M. is the first patient included in our study, his blood is positive for P. falciparum according to the rapid diagnostic test (see above) and harbours gametocyte transmission stages. He is a quiet 11 year-old boy. I first bring him to the insectary with his mother and explain the procedure in simplified French; I then carry out a mosquito feed on myself to demonstrate how simple the procedure is to both of them. After taking a blood sample in the clinic, I bring him back to the insectary for the mosquito feed.

We place two pots of mosquitoes on M.’s calves, the 5-minute feed seems endless in spite of the microscopist’s and my efforts to distract M. from the itch. M. comes back the next day and I realise I had been wrong, far from quiet, M., now free of malaria, is joking around and curious to understand the function of literally every piece of equipment in the insectary. M. now frequently visits us at the insectary with a few of his friends. On their last visit I was transferring samples to the liquid nitrogen tank and they were observing the fog bubbling out of the container from a distance. Although this will need replication, I think I made an initial discovery: liquid nitrogen has a universal appeal.

m-photo

M. outside the insectary

Since M.’s first visit, we have treated 800 patients and included more than 20 in the study and the protocol has become a lot smoother. We hope to get some indication as to the hidden biology of the sexual stages of malaria within the next 6 months.

As malaria biologists, we sometimes get lost in the fascination of studying biological problems, and lose touch with real world issues caused by these deadly parasites. Coming to work every morning for the past weeks to witness dozens of febrile children waiting for treatment has served a powerful reminder of the real burden of malaria and the importance of ridding the world of this affliction.

About the author:

Arthur Talman is a postdoc in Mara Lawniczak’s group at the Wellcome Trust Sanger Institute. By combining single cell transcriptomic approaches in the lab and molecular characterisation of parasites collected in Africa, he is investigating the human reservoir of malaria parasites and their transmission to mosquitoes.

Related publication:

Mara K. N. Lawniczak and Philip A. Eckhoff (2016) A computational lens for sexual-stage transmission, reproduction, fitness and kinetics in Plasmodium falciparum.  Malaria Journal DOI 10.1186/s12936-016-1538-5

Further links:

Human intestinal microvilli. Credit: Wellcome Library, London
Sanger Life

Great balls of cells: Using intestinal organoids to study Salmonella

DATE: 10/09/15

By Jessica Forbester

Intestinal human organoids. Credit: Jessica Forbester

Intestinal human organoids. Credit: Jessica Forbester

One of the main causes of food poisoning is Salmonella enterica. This bacterium infects cells in the intestinal epithelium that lines our gut, leading to painful stomach cramps, diarrhoea and fever. One major difficulty in studying Salmonella infection is that you can’t easily study it in people’s intestines, and recreating the intestinal epithelium in a lab setting has been notoriously tricky. However, newly developed intestinal organoids are starting to provide a solution.

Intestinal organoids are little balls of intestinal epithelium, composed of a range of intestinal cell types surrounding a hollow lumen. The organoids act as a bridge between in vivo and in vitro systems.

The intestinal epithelium is an extremely important part of the immune system, with a complex structure and range of cell types. It acts as the dividing barrier between the space inside the gut tube, called the intestinal lumen, and the underlying gut tissue.

I have been generating intestinal human organoids (iHOs) from human induced pluripotent stem cells (hIPSCs). Using a protocol established by our collaborators Ludovic Vallier and his team at the Anne McLaren Laboratory for Regenerative Medicine, I take these stem cells and expose them to different chemical signals. This drives changes in gene expression, which pushes the hIPSCs to change into more specialised cells, in a process known as differentiation. The cells change first into endoderm, and then into hindgut.

To grow the balls, I place this hindgut into a pro-intestinal culture system, with a supporting Matrigel matrix. Growth factors that promote intestinal differentiation and proliferation are added to the media and, after a few weeks, little spheroids start to form.

These balls of cells are self-sustaining and can be grown for long periods of time. They take a while to mature and form structures recognisable as adult cells but, after a few months of intensive culturing, I get intestinal human organoids that are ready to work with. They can then be used as an infection model for enteric pathogens such as Salmonella.

Salmonella enterica serovar Typhimurium causes a self-limiting gastroenteritis in healthy individuals. We wanted to use intestinal human organoids to show the early interactions between S. Typhimurium and the organoids generated from a representative hIPSC-line called A1ATD-1.

Firstly, we had to ensure that the organoids contained different cell types normally found in the intestinal tract, such as Goblet cells and Paneth cells. Specific cell type markers were detected with RT-qPCR, and immunostaining showed the localisation of these markers within different groups of cells. Using transmission electron microscopy we could see clear polarisation of the cells, microvilli and tight junctions, confirming we were growing organoids that displayed characteristics of human intestinal epithelium.

S. Typhimurium would normally interact with the epithelial cells at the luminal side. The bacteria therefore needed to be delivered directly into the luminal cavity of the organoids; the centre of the sphere. This required multiple microinjections of the bacteria into the iHOs before we could collect enough RNA for RNA-Sequencing. After sequencing, we saw previously well-described responses to S. Typhimurium such as up-regulation of proinflammatory cytokines. However, genes such as BIRC3 and IL-20, whose role in Salmonella infection is not well understood, were also flagged. Interestingly, BIRC3 protein is also expressed in enteroendocrine cells, which may shed light on their role in response to intestinal infection.

Many people here at the Sanger Institute are generating human induced pluripotent stem cells so we have a large pool of genotypes to select from. We can therefore utilise our iHO system to help understand how the host genotype can alter the response of the host intestinal epithelial cells. This is a really exciting prospect as this response is crucial to the outcome of an infection, and this work provides support for using iHOs as a tool to study host-pathogen interactions at the intestinal interface.

Jessica Forbester is a PhD student at the Wellcome Trust Sanger Institute, working under the supervision of Gordon Dougan.

References:

Forbester et al. (2015). Interaction of Salmonella enterica serovar Typhimurium with intestinal organoids derived from human induced pluripotent stem cells. Infection and ImmunityDOI:10.1128/IAI.00161-15

Hannan et al. (2013). Generation of multipotent foregut stem cells from human pluripotent stem cells. Stem Cell Reports. DOI:10.1016/j.stemcr.2013.09.003

Related Links:

Sanger Life

A world without smell

04 April 2015
By Darren Logan

A family tree showing the incidence of anosmia in five generations of the same family.

A family tree showing the incidence of anosmia in five generations of the same family.

We generally do not think about our sense of smell too often. Yet it contributes hugely to the multi-sensory perception of our world.

For example, approximately 80 per cent of the flavour of our food relies entirely on smell; without it we are restricted to just five basic tastes.

Most of us will have experienced this when suffering a heavy cold, when our noses are completely blocked, meals are bland and unappetizing.

In addition, we routinely use smell to warn of danger and signal safety, to attract partners and customers (think ‘new car smell’) and to evoke memories.

In fact, olfaction, the technical term for our sense of smell, is sufficiently important to us that the molecular odour receptors in our nose are encoded by the largest single family of genes in our genomes.

So, what happens if you lose your sense of smell or if you were born without it? Having had a research interest in sensory genetics for a number of years, I knew that such a condition, called anosmia, existed. However, like most of us, I had never really considered the profound and disconcerting affect the absence of smell may have on everyday life.

I recently visited Fifth Sense, a charity supporting people with smell and taste disorders. One member, Sarah Kathleen Page, a photographer who was born with anosmia, summed up life without smell:

“We cannot smell the gas leak slowly filling up our home, we cannot smell our newly born daughter, we cannot fully enjoy the sensory pleasures most people take for granted. We hope for a doctor that believes us when we say we cannot smell and long for a friend that never forgets. Without someone to say, ‘I understand, I believe you and I will do my best to help’ we live in a very lonely world.”

To better understand this disorder, my laboratory has begun a study to find the genetic basis of being born without the ability to smell. Along with colleagues at the Monell Chemical Senses Center in Philadelphia, we launched a social media campaign to find families with people who can and cannot smell across multiple generations. We received responses from across the world.

In one case, we found a family with anosmia across five generations; each time, the condition was inherited from parent to child. After carefully mapping out the family trees, we carried out a standardized smell test on each family member to confirm the diagnosis. We then collected saliva and are now sequencing their genomes.

Using a strategy developed at the Wellcome Trust Sanger Institute to successfully identify the genes involved in other rare diseases, we will compare the genetic variation from those within the same family who can and cannot smell. This approach helps narrow down the search for the precise gene responsible.

Identifying the genetic causes of anosmia is only the first step in a long journey. Like many rare genetic conditions, it is unrealistic to expect that new treatments or cures will automatically follow. However, we aim to press on and investigate how these genes contribute to the complex neural circuits that connect our noses and brains. Only then can we evaluate them as potential targets for clinical intervention.

Darren Logan joined the Wellcome Trust Sanger Institute faculty in 2010. His team – Genetics of Behaviour – combines comparative genomics, reverse genetics, behavioural testing, and neural activation studies to identify and investigate genes involved in the signalling, sensing and processing of olfactory cues that influence behaviour. They aim to understand the role of these genes in instructing normal perception and behaviours and their dysfunction in neurological disorders.

Related Links:

Sanger Life

The home of genetic sequencing

05 March 2015
By Anita Sedgewick

Fred Sanger, the father of DNA sequencing. Credit: Genome Research Limited

Fred Sanger, the father of DNA sequencing.
Credit: Genome Research Limited

This weekend a blue plaque will be unveiled to honour the scientist who gave his name to the Sanger Institute. Fred Sanger won the Nobel Prize not once, but twice – in 1958 for his work on the structure of proteins and in 1980 for his work on DNA.

The plaque is being unveiled at 11am on Saturday 7th March, at 252 Hills Road in Cambridge, the Sanger family home where Fred lived when he won both Nobel prizes. His children recall it as his place of rest and retreat, where he returned to from the laboratory for his lunch or evening meal, and where he often continued to work in the evening. Professor Julian Parkhill from the Sanger Institute will be speaking at the ceremony, along with Fred’s son, Robin Sanger.

The plaque is one of ten being installed across the UK by the Society of Biology, as part of its Biology: Changing the World project. This project is honouring the eminent and sometimes unsung heroes of biology.

On Saturday 7th March a plaque celebrating Fred Sanger will be unveiled at his former home in Cambridge. Credit: Society of Biology

On Saturday 7th March a plaque celebrating Fred Sanger will be unveiled at his former home in Cambridge.
Credit: Society of Biology

From the man who established the Natural History Museum to the woman who increased our understanding of rheumatoid arthritis, and the team who worked on the first mammal to be cloned from an adult cell – Dolly the sheep –the plaques aim to give some of the leading biologists from the past the recognition they deserve.

As part of the project, a website has been developed to celebrate the famous and not-so-famous biologists of past and current times, along with links to many of the plaques and statues that commemorate them. A free app is also available to download in the Apple and Android stores.

The project is also hoping to inspire the biologists of the future. Scientists, students and teachers have been interviewed about who first inspired them with a passion for biology. Teaching resources have been developed that are aimed at 7-11 year olds, but the website and app can be used with students of all ages.

Anita Sedgewick is a Project Manager at the Society of Biology. She leads the initiative ‘Biology: Changing the World’, which aims to honour biologists who have made a significant contribution to the field.

Related Links:

Sanger Life

Battling bacteria: this time it’s personal

24 November 2014
By Claire Chewapreecha

Claire Chewapreecha (front row, far left) received an Anglo-Thai Society Education Award for Medical Science in recognition of her work on Streptococcus pneumoniae earlier this month.

Claire Chewapreecha (front row, far left) receiving an Anglo-Thai Society Education Award for Medical Science in recognition of her work on Streptococcus pneumoniae.

I was born in Thailand and I am committed to improving public health in Southeast Asia through research into the genetics of bacteria that cause an enormous disease burden in the region.

Under Professors Julian Parkhill and Stephen Bentley’s kind supervisions, my phd research at the Wellcome Trust Sanger Institute centred on the use of genome sequences to understand the evolution of the bacterial pathogen, Streptococcus pneumoniae (the pneumococcus), which causes 1.6 million deaths worldwide each year. Despite high casualties, treatments have become more difficult as the pathogen rapidly develops antibiotic resistance.

To conduct this research, we used a collection of over 3,000 pneumococcal isolates from a refugee camp on the border of Thailand and Myanmar through our active collaboration with Drs Paul and Claudia Turner. It was a great privilege to work on this project, having seen first-hand how pneumococcal infections had affected people at the camp.

The analyses highlighted recombination, a process by which the bacteria exchange their genetic contents. This mechanism allows the species to adapt rapidly, developing resistance to the antibiotics we use to treat infections. This finding was published earlier this year, and voiced the concern over rapid spread of antibiotic resistance in this region.

To aid clinical surveillance of resistant bacteria, I further identified genetic determinants of antibiotic resistance. Genome-wide association study (GWAS) was employed to locate the single-nucleotide changes in the DNA code of the bacterium that enable it to evade antibiotic treatment. The technique has been used to identify genetic causes of disease in humans but was thought to be impossible to use on bacterial DNA until recently.

Based on collaborative links between Department of Medicine, University of Cambridge; the Wellcome Trust Sanger Institute in UK; and Mahidol University in Thailand, my postdoctoral project will focus on the evolution of another pathogenic bacterium, Burkholderia pseudomallei. The pathogen causes melioidosis, a disease endemic in many agricultural areas with particular importance in Southeast Asia.
I hope that a better understanding of this bacterium will help prevent infection and improve patient outcomes.

This month I have been honoured to receive an Anglo-Thai Society Education Award for Medical Science in recognition of my work on Streptococcus pneumoniae. This work would not be possible without strong support from my supervisors and colleagues who offer insightful and invaluable advice, and keep me going when times are tough.

In 2017, I will return to work in Bangkok, the city where I grew up, to continue my research and to pass on the expertise I have gained from my research at Cambridge University and the Sanger Institute.

Claire Chewapreecha recently completed her PhD at the Wellcome Trust Sanger Institute in the Pathogen Genomics Team. She received an Anglo-Thai Society Education Award for Medical Science in recognition of her work on Streptococcus pneumoniae earlier this month.

References

  • Chewapreecha, C et al (2014). Comprehensive Identification of Single Nucleotide Polymophisms Associated with Beta-lactam Resistance within Pneumococcal Mosaic Genes. PLOS Genetics. DOI: 10.1371/journal.pgen.1004547
  • Chewapreecha, C et al (2013). Dense genomic sampling identifies highways of pneumococcal recombination. Nature Genetics. DOI:10.1038/ng.2895
  • Chewapreecha, C (2012). SDF-Genome Watch: Natural transformers. Nature Reviews Microbiology . DOI:10.1038/nrmicro2865

Related Links:

Don’t miss your chance to be the expert for your own story. Credit: Shutterstock, dny3d
Sanger Life

Science and the media – allies or enemies?

05 November 2014
By Rebecca Gladstone

Don’t miss your chance to be the expert for your own story. Credit: Shutterstock, dny3d

Don’t miss your chance to be the expert for your own story. Credit: Shutterstock, dny3d

On Friday 3 October I had my preconceptions of science media, and my roles and responsibilities in relation to it challenged. So much so that I am now writing my first blog piece. Here’s why I am going to be Standing up for Science.

At the Standing up for Science media workshop run by Sense about Science, myself and 39 other early-career researchers were asked what could we do to address scientific misconceptions and misinformation. Hearing first-hand from scientists who have chosen to be involved with or who have been thrown into a science news story did a lot to dispel the usual urban legends of science-story hell. They had not only survived but are passionate about engaging with the media again and again.

We also shared our experiences with a variety of actual journalists who had reported science for publications such as the Sun, right through to specialist environmental blogs. A shockingly obvious message was that journalists are people. Overwhelmingly, they are people who are trying to get it right and do their best!

If not me, then who?

Researchers are the experts. This is true even at PhD level; it can often be said that you know more about the details of your project than your supervisor, who is never omnipotent, although I’m sure they’d like you to believe it. The point is that we have the best understanding of our subject area and, consequently, a greater chance of passing on clear, factually correct information. Conversely, if we don’t speak then it is left to those less qualified. Definitely be ready to discuss your own work but also think about standing up to the science story that makes your blood boil!

If not now, when?

Contrary to popular belief, scientists and journalists do live on the same planet, but what is important is that we are worlds apart when it comes to deadlines.
For starters, deadlines in journalism are not only real but also fast and frequent. News is only news today and it won’t be waiting for us to finish all our other scheduled tasks before it goes to press. Don’t miss your chance to be the expert for your own story. If you see a science story in need of some factual context there is a window of opportunity to kill a story before it snowballs, you can respond, but it’ll have to be today!

Are we missing the point of science?

Science coming from the Latin scientia, means knowledge. We are busily generating new knowledge day in day out. But who is this knowledge for? In my opinion we are contributing to the greater good and science is for everyone. In fact, many of us are working on projects that are dedicated to improving public health, some will receive public funding and almost everyone now in the era of public engagement is asked to demonstrate a component of outreach within their grant proposals.

Shouldn’t we seriously consider our role in facilitating the dissemination of our science further than to our peers? The truth of the matter is that the media is an excellent channel for communicating with non-scientists and we have a duty to help get good science out there.

There is help and advice for getting started out there. Like me you can make contact with you press office and Sense about Science to learn more.

Rebecca Gladstone is a Senior Bioinformatician in the Pathogen Genomics group at the Wellcome Trust Sanger Institute, where she is currently working on a global collection of 20,000 pneumococcal genomes to assess pneumococcal vaccine impact. Rebecca is interested in learning how to better share the research findings with the public. She Tweets as @becctococcus.

Related Links:

Colin Barker and his Colinator Colony Picking Robot
Sanger Life

Colin’s Colony Collecting “Colinator” minimises mindless monotony

Colin Barker and his Colinator Colony Picking Robot

Colin Barker with ‘The Colinator’ colony picking robot. Credit: Genome Research Limited

18 July 2012

Written by Colin Barker

I’m an engineer at the Sanger Institute and I’m often asked to work with scientists to find new ways to make research techniques faster, more efficient and, sometimes, a whole lot less boring.

About two years ago, Bill Skarnes (who leads the stem cell team) asked me to build a robot to help with the colony picking process. It is a dull and monotonous task that is also labour intensive and highly repetitive – an ideal process to be given to a robot. The team works with colonies of stem cells that are grown for a few days and then need to be identified, isolated and separated in the space of just 24-48 hours. This need to separate out the colonies is a major bottleneck in the research process.

So that I could create a robot that will mimic the way the researchers work in the most appropriate fashion, I sat in the laboratory clean rooms observing the researchers in action. I rapidly realised that this was a highly skilled and delicate operation and that a robot would never be able to fully replace the researchers’ expertise. Knowing which colonies to pick, and which to leave, is a skill that is best left to the scientists.

However, I knew that if I could automate the rest of the process I could help bring benefit in several ways. My robot would relieve RSI caused by repeated pipetting to aspirate and separate colonies, remove the eye strain of peering down a microscope, and save valuable time by freeing researchers to do other, more creative, tasks. The challenge was set.

I worked closely with Wendy Bushell from the ES Cell Mutagenesis team to design ‘The Colinator’ – a robot that accurately picks 96 colonies in under 14 minutes, to an accuracy of less than the width of a human hair. It uses an image detection system to highlight colonies on screen for the researcher to choose. Once the best colonies have been chosen, the Colinator gently slices, slides and lifts each colony away from the plate using a syringe needle with an accuracy and reliability of close to 100 per cent. The picked colony is then dispensed into a well, and the needle is washed clean before returning to pick another one. Not only does the robot enable researchers to continue with other tasks, but the gentle picking process keeps the colonies intact and increases the cells’ ability to grow and thrive.

The Colinator will soon be working full time in the Sanger Institute laboratories, but the story doesn’t end there. We are now working with a commercial partner to turn the Colinator into a line of machines that can be used in labs around the world to free researchers from monotonous colony picking tasks. Watch this space, as they say.

Colin Barker is an engineer at the Wellcome Trust Sanger Institute… more

Related Links