Cryo-EM takes centre stage

Posted on October 17, 2017 by James Streetley

A few weeks ago, the Nobel Prizes for 2017 were announced. This year, 3 of the founders of the field I work in – cryo-EM – were honoured with the Nobel Prize in Chemistry for their work in developing the technique of cryo-EM into something now used near routinely in labs around the world.

After the news was announced, I was asked to write a short explainer/news piece about the technique for the website The Conversation. The Conversation is a website where academics team up with professional editors to write and publish articles, so it was really nice to be asked to write for them. The resulting article is published under a Creative Commons CC-BY-ND licence so can be reused anywhere, so I’ve taken the opportunity to archive it here:

Trio behind method to visualise the molecules of life wins 2017 Nobel Prize in Chemistry

James Streetley, University of Glasgow

Three scientists have won the 2017 Nobel Prize in Chemistry for developing a technique that helps image biological molecules in unprecedented detail. Jacques Dubochet, from the University of Lausanne in Switzerland, Joachim Frank, from Columbia University in the US, and Richard Henderson, from the MRC Laboratory of Molecular Biology in the UK, will share the prize sum of £831,000.

A predecessor of their method – which is known as cryo-electron microscopy – has been recognised by the Nobel committee before. The 1986 Nobel Prize in Physics was given in part to Ernst Ruska for inventing the electron microscope.

As a concept, the electron microscope is similar to a light microscope – a beam is shone through a series of lenses, then through the sample and more lenses, to form an image on a piece of film or camera sensor. Of course, in the electron microscope we are shining a beam of electrons rather than light through our sample.

Unlike light, electrons can’t travel through air – they would collide with the air molecules and get diverted away. This means the electron beam must be contained within a high vacuum system so there are no stray particles to interact with the beam. The lens system is formed of coils of copper rather than the glass lenses of a light microscope – like air, glass would scatter our beam of electrons, rather than focusing it. Instead, we can apply current through the coiled-copper lenses to create a magnet, and we can focus and shape our beam using this magnet instead.

Richard Henderson from the UK is one of this year’s chemistry winners.
MRC/UNIVERSITY OF CAMBRIDGE/EPA

However, the need for a high vacuum within the microscope affects what samples can be imaged. Samples need to be dry as liquids would instantly evaporate in the vacuum. Methods for preparing a biological sample like this are to dry them in a protective stain layer or embedding it in resin. However, such dehydration techniques don’t allow us to make the most of the microscope and see the finest details in our sample.

A new era of biochemistry

Cryo-electron microscopy eliminates the need for dehydration. Biological samples such as cells, viruses or proteins are simply frozen within the liquid they are in. As long as we keep the sample frozen in the microscope, the ice protects it from the harsh effects of the vacuum. However, we can’t form just any type of ice. It must be vitreous ice.

This ice doesn’t form crystals, like in a home freezer, where the water molecules rearrange into an ordered pattern. Instead, they are frozen fast enough that they stop moving as they were. It is as if we hit the pause button on liquid water. It was the discovery of how to create vitreous ice that earned Dubochet his share of the prize.

Since then, many laboratories around the world have adopted the technique of cryo-electron microscopy, aided by semi-automated machines for preparing samples within vitreous ice. The earliest work began with looking at viruses, but advances in microscopy and related technologies has seen this expand across a whole size range from tiny individual proteins (around a millionth of a centimetre), through to “molecular machines” consisting of proteins assembled together. “Motor proteins”, such as myosin, are examples of molecular machines – they are responsible for muscle contraction. It is also possible to image bacteria and sections of human cells.

By analysing these images with computers we can calculate how the particle would have looked in 3D in order to produce that image. It’s similar to looking at a shadow and working out how the object that made it looks. Devising methods to do this is part of what Frank was honoured for.

Once we have a 3D model for how a virus or molecular machine is structured, we use that to understand how it functions. Henderson was the first to show that cryo-electron microscopy could be used to obtain the most detailed of 3D models – at atomic resolution. Often, other laboratory methods can tell us “what” a molecular machine does, but with detailed 3D models, we can look inside these machines and understand “how” they do it.

3D image of the Giant Mimivirus.
Structural Studies of the Giant Mimivirus. PLoS Biol 7(4): e1000092. doi:10.1371/journal.pbio.1000092, CC BY-SA

Having a basic understanding of how these machines work, we can start investigating diseases. What happens when such machines don’t work? Or in the case of bacterial or viral infection, what can we do to disrupt their molecular machines? A recent example of this is the Zika virus: scientists used cryo-electron microscopy to rapidly determine the structure of the Zika virus last year. This has already led to follow-up research looking at how to find drugs against the virus. Scientists have also managed to look at proteins involved in antibiotic resistance using this method.

The technique is already achieving results that were unthinkable a few years ago – both in terms of the small size of biological molecules that can now be imaged, and in the detail that can be seen in them. Future advances will continue to widen the possible samples that the microscope can be applied to: small, irregularly shaped objects, molecules only present in small amounts, looking at mixtures of particles or even molecules still present within cells.

James Streetley, Post-doctoral researcher, University of Glasgow

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

University of Glasgow Public Holiday Calendar

Posted on March 5, 2015 by jstreetley

After searching for a public calendar with all the University of Glasgow public holiday dates in, I thought I’d share my own in case it’s useful to anyone else.

Simply add this link to which ever calendar program you use.

I’ll endeavour to keep it up to date when the University next updates their list of public holidays.

The end draws near – the PhD viva

Posted on September 25, 2014 by jstreetley

Submitted PhD thesis

A few months ago, I submitted my PhD thesis. After all of the preparation and writing, submitting was somewhat of an anti-climax. This is because submitting those nicely bound volumes means nothing unless someone is going to read and examine them to determine if the work they contain will earn you the degree and the right to call yourself Dr.

In the UK, these examinations often happen some time after submitting, in a process known as the viva. These exams involve the examiners coming to the university/institute and conducting a private, face-to-face examination of your knowledge and the work presented in the thesis, often over a number of hours.

All this is purely explanation of the main point:

I had my PhD viva on Monday and I passed!

I passed with the most common outcome; minor corrections. This means that whilst I have passed, the examiners would like some changes to be made before the final version of record is submitted. It is only when they are happy with those changes that I will officially earn the degree.

For now, I’m beginning to come down from the celebrations and start working towards the corrections. So it is still not yet the end; I think the real closure will happen when the award letter and certificates are in my hands.

New Site

Posted on July 10, 2014 by jstreetley

Announcing the launch of swim.bike.run.blog!

I’ve decided to split all the triathlon/racing blog posts away from this website, and keep it more a personal website with a few blog posts, rather than having regular sporting updates on it. So old posts should already by redirected to their new homes at swimbikerunblog.co.uk, and new race reports and other triathlon thoughts will start to appear there.

Here on jstreetley.co.uk, I will keep my CV and the other more general or sciencey type thoughts that used to be here before all that sport took over.

3 years and 9 months

Posted on June 20, 2014 by jstreetley

Submitted PhD thesis

Yesterday, I submitted my PhD thesis! The culmination, to the day, of 3 years, 9 months of work, distilled into 145 pages. It means that I can now return to “normality”, having become somewhat of a hermit over the last month whilst I pulled out all the stops to get it completed.

It’s a great relief, and I hope I don’t need to write a document that long again for a while. It’s also not over yet though. For those who don’t live in the academic bubble, I just thought I’d explain what this means, and after what point I’ll officially “get” the degree.

What happens next?

Currently, the university is looking after my two submitted copies, until two people (one within UCL and one from outside) can be found to conduct an examination. They will then read the thesis and after that, the 3 of us will sit down in a room and they’ll question me on it – this is the oral exam or ‘viva’.

The outcome of this meeting will decide whether or not I am awarded a PhD. The most common outcome is “minor corrections”, where the examiners will award the PhD on the condition that various mistakes are corrected or additional information added before the final version of record is produced. This is version that will end up in the library at UCL. Once the examiners have approved those corrections; then I’ll be Dr James. So it’s not over yet, but the end is in sight 🙂

Save the UCLU Garage Theatre Workshop

Posted on February 14, 2014 by jstreetley

Save your student theatre

During my time at UCL as an undergraduate, I was lucky enough to be involved with a fine bunch of people; the UCLU Stage Crew society. These ladies and gents use their spare time to help other students put on shows; musicals, dramas, fashion shows, jazz concerts, opera, bongos(!). You name it, they’ve assisted with it.

They also run a small ~70 seater theatre on the ground floor of the one of the college buildings, the UCLU Garage Theatre Workshop. And by run, I mean everything from the year’s budget to keeping the backstage toilet clean and functional. It sounds like great fun, and it was, but now this is under threat from UCL.

The college, somewhat reasonably, would like to renovate the space. However they are refusing to replace what they are taking with an alternative space.

I think this would be a great shame, because as well as being immense fun, I think the theatre is a very valuable asset to the university and student body. I can say with certainty that I would not be the person am I today, in the position that I am in, had that theatre not existed. And I can point to dozens, if not hundreds, who could say the same.

A few benefits are obvious: having a place to perform, try out small-scale projects and get your work seen by an audience without using the college’s larger (and more expensive) Bloomsbury Theatre is a benefit in its own right. But actually, aside from the considerable artistic merit and cultural benefit, working on a theatre project gives students the opportunity to learn many skills that are missed by an academic education.

On a personal level, I believe I developed many skills whilst working in the Garage:

speaking and performing develop self-confidence and public speaking, something directly related to giving talks or presenting in an academic context
teamwork is a vital skill for putting on a production, between designers, technicians, cast members, musicians and the director. Having a concrete example of working in a team to achieve a goal is invaluable to employers.
leadership goes hand-in-hand with teamwork, and being given a role of responsibility such as Garage Theatre Manager or Technical Manager is a good way to gain managerial experience as an undergraduate.
committee work is a strong component of running the theatre; allocating time, money and people to productions were all decided by committee.
personal organisation is key when running a theatre or rehearsing a show in your spare time, whilst also concentrating on a degree course.
budget management for shows in the Garage is important as the shows are often on a very restricted budget
bidding for funding is important for all clubs and societies, but the Garage has been traditionally successful in applying for extra funding for equipment, and this sort of ‘writing to persuade’ is very important in many jobs and even in getting a job, so honing it at the student union can only be a good thing.

These are some of my personal and less obvious ways I think a student theatre helps develop the skills and further the education of the student body. There are probably many others that I’ve missed. But I do think that a university should encourage students to gain all of these skills and that being involved in the Garage is brilliant way to do that.

The facebook page is doing a good job of collating videos and pictures of the Garage in action and I hope they can put together a persuasive case to the College and also persuade UCLU to give the campaign their full support. It has already gone out in the all student email, so I am hopeful that the union will be able to lobby the College too.

Katherine Esau – Ada Lovelace Day 2013

Posted on October 15, 2013 by jstreetley

This is the first year that I’ve participated in Ada Lovelace Day, and I decided to pick a woman from history, related to my own field and who I’d not heard of previously, so that I’d have to do some research. I came across the plant anatomist and later electron microscopist, Katherine Esau.

Katherine Esau

Katherine Esau working at the electron microscope – Copyright Cheadle Center for Biodiversity and Ecological Restoration

Katherine Esau was born in the city Yekaterinoslav, in the then Russian Empire (now Dnipropetrovsk, Ukraine) in 1898. It was in Russia that she received her early education, until 1917, when the Russian revolution and later German occupation of Ukraine prevented her from completing her studies at the Golitsin Women’s Agricultural College, Moscow.

Esau and her family fled to Germany, moving to Berlin. Here, she was able to continue her studies by enrolling at the Berlin Landwirtschaftliche Hochschule (Agricultural College), completing them in 1922.

Later in 1922, the Esau family moved again, this time to California, USA. It is here that Esau made home for the rest of her life. After some short term jobs, her research career began in earnest with a job at Spreckels Sugar Company. Her project was to develop a sugar beet resistant to curly top disease, a virus carried by beet leafhoppers. This research led to her gaining a position doing similar research as a graduate student at UC Davis in 1927.

Unfortunately (or perhaps fortunately, given Esau’s later success), this project turned out not to be viable at UC Davis, and Esau’s attention was turned to plant anatomy and the effect of the curly top virus on the plant. For this research she was awarded a PhD in 1931.

Esau stayed within the University of California for the rest of her career, first at Davis and later at Santa Barbara, and continued researching the same themes; plant anatomy and virus-plant interactions. In particular, Esau studied the phloem, the tissue that distributes nutrients throughout plants and how viruses such as curly top use this to spread, as well as studying healthy plant anatomy.

My interest in Esau comes from her later work, setting up an electron microscopy laboratory and using this technique to study virus-diseased plants. These are techniques not a million miles away from those I use to look at cells today. Much of this work was carried out after Esau retired, as despite retiring in 1965, she continued to work for many more years, including supervising PhD students.

In addition to her research and teaching, Esau also wrote and illustrated two key textbooks in plant anatomy; “Esau’s Plant Anatomy” and “Anatomy of Seed Plants”, both of which continue to be on university reading lists today, amongst many other books and publications.

During her career, Esau picked up many awards for her work, including the National Medal of Science in 1989, Certificate of Merit from the Botanical Society of America in 1956, and election to the National Academy of Sciences in 1957. She became only the sixth woman to be elected to the Academy. She was also president of the Botanical Society of America and now gives her name to one of their awards, the Katherine Esau Award, given to “the graduate student who presents the outstanding paper in developmental and structural botany” at their annual meeting. UC Davis also runs a post-doctoral fellowship in her name.

As part of her autobiography and oral history in 1991, David Russell asked her about women in science and her experience:

When I first arrived in the United States, many people expected me to do just ordinary things, housework and getting married and so forth—the same routine. But I was more ambitious.

and

I never worried about being a woman. It never occurred to me that that was an important thing. I always thought that women could do just as well as men. Of course, the majority of women are not trained to think that way. They are trained to be homemakers. And I was not a homemaker.

However, on promotion and her former boss, Esau says;

I now learn from people that he actually did not like to have a woman in the department. He did not treat me right, but I didn‘t notice it. I thought that was the way it was done. I never even questioned it. For example, he was very reluctant to give promotions. Nowadays they often jump one step, and people just go right through the appointments very quickly. But at that time, we went six years in each grade. Six years. It never changed. But then when a new director arrived on the campus, he looked at my record and said that I was not getting enough salary. So he raised my salary, but our chairman, Dr. Robbins, would not do it.

And thus demonstrating, in her own words, why we need initiatives such as Ada Lovelace Day and Athena SWAN.

References and further reading

Biographical Memoir from the National Academy of Science
Autobiography and oral history from UC Santa Barbara
Katherine Esau digital archive from Cheadle Center for Biodiversity and Ecological Restoration
Katherine Esau on Wikipedia (this article could do with some love!)

About Ada Lovelace Day

Ada Lovelace (1815-1852) is known as the world’s first computer programmer for her work with Charles Babbage on his Analytical Engine. She gives her name to a Ada Lovelace Day, in mid-October each year where we “celebrate the achievements of women in science, technology, engineering and maths” (STEM). The day is generally marked by people creating and sharing blogposts, videos and other material about an inspiring woman in STEM.

Get Britain Cycling debate in Parliament

Posted on July 22, 2013 by jstreetley

The ‘Get Britain Cycling’ report by the All-Party Parliamentary Cycling Group has secured a debate in the House of Commons on the 2nd September. Having previously written to my MP, Frank Dobson, about cycle safety and received a lukewarm response, I’ve decided to try again.

My letter, which is a personalised version of the one British Cycling provide, is below. I shall update with a response, if I get one.

Dear Mr Dobson,

You may recall that I wrote to you back in November last year to draw your attention to The Times newspaper’s cycle safety campaign ’Cities fit for Cycling’. Following this campaign and the ’Get Britain Cycling’ report recently released by the All-Party Parliamentary Cycling Group, there will be now be a debate in the Main Chamber on the first day after the summer recess, 2nd September between 7 and 10pm. As one of your constituents I urge you to attend.

We are lucky to live in one of the better areas in London for cycle infrastructure but even with this there is still work to be done, as the recent death of a cyclist in Holborn shows. In your previous letter to me you referenced cyclists jumping red lights. I understand that this is a nuisance for many, but this is no reason not to help the vast majority of law-abiding cyclists to have more space and safer routes.

Cycling has enormous potential benefits, for our health, our economy, our environment and our quality of life. Now is an ideal time to start realising those benefits, with interest and participation in cycling at an all-time high following Britain’s Olympic and Tour de France successes. The Times’ ‘Cities fit for Cycling’ campaign has also galvanised support for better conditions for cycling; nearly 70,000 people have signed the e-petition and the report has received support from David Cameron, Nick Clegg, Ed Miliband, Sir Dave Brailsford, Sir Richard Branson, Lord Sugar and Edmund King.

To date, there has been no clear announcement on the Government’s plan for cycling and this is a chance to demonstrate that Parliament understands the countries need for political leadership to make cycling all it can be in this country. This report sets out a clear action plan and has received near unanimous support.

The ‘Get Britain Cycling’ report recommends an increase cycle use from less than 2 per cent of journeys in 2011, to 10 per cent of all journeys in 2025, and 25 per cent by 2050. Around the country communities are looking for leadership on this issue and to be effective the next steps must be led from the very top.

Key priorities from the report include:

Ensuring that cycling is designed into all future roads, junctions and relevant transport policies

20mph speed limits in urban areas and lower speed limits on many rural roads

All children to be given the chance to learn the skills of road cycling, at primary and secondary school

Government funding on cycling to be £10 per head of the population

I hope to see your contribution to the debate, ensuring the cycling boom in London can will continue and improve life in the capital for all.

EDIT: Just found this Research Briefing Note on UK road cycling by the House of Commons Library. It contains a breakdown of cycling injuries by constituency. I wish I’d pointed this out to Mr Dobson in the letter, as our constituency does not come out well from this.

UPDATE 25/08: Yesterday, 24th August, I received a response from Frank Dobson, which is below:

Thank you for your recent letter about cycling safety.

There have been many well reported cycling fatalities on London’s roads of late, including the fatal accident on Holborn some weeks ago. Irrespective of whether of not the extra reporting of these deaths reflects an actual increase in the number of accidents, it is clear that more must be done to improve road safety for cyclists, as well as for other road users.

Whilst it is undoubtedly true that we were already some way behind the safety standards of some other Europeans[sic] nations, I feel that part of the problem may also lie in the confused cycling policies that have been introduced by the Mayor of London who has done little to improve cycler[sic] safety. Many of his policies are actually having the opposite effect.

The introduction of the Cycle Superhighways, for instance, has encouraged cyclists onto dangerous and busy roads, with the sole protection being provided by a thin strip of paint. Unsurprisingly, this policy has already led to several collisions and deaths, with Cycle Highway[sic] 2 having recently been branded as “far from fit for purpose” by a group of air ambulance emergency care doctors.

Little has also been done to improve the safety of cyclists using the deliberately mistitled “Boris Bikes” with the Mayor repeatedly rejecting calls for them to be provided with helmets, despite the obvious added safety that this would provide.

Cycling in London needs an overall strategy and a cycling network instead of a patchwork. Boris Johnson once claimed that a “critical mass” of cyclists would make the roads safer, but it is clear we need more than catchphrases from spin doctors if we are to improve safety on London’s roads. I have therefore written to the Mayor of London to ask what steps he is taking to address these issues and will write to you again once I have received a response.

With so many points to address in this letter, I’m almost not sure where to start. The fact that he doesn’t reply to any of the points in my letter suggests this is a form letter sent in reply. On the one hand, this is positive, as to receive so many letters about cycling as to warrant a standard response means it must be on his radar. On the other hand, I am disappointed that he has not mentioned whether he will attend Parliament next week for the debate.

By lambasting the Cycle Superhighways as having the “sole protection…a thin strip of paint”, I can only assume he supports a full “Dutch-style” segregation and the LCC’s “Love London, Go Dutch” campaign.

The letter then veers off into the helmet debate, the benefits and disadvantages of which I don’t want to get into. Suffice to say, it isn’t always as obvious you’d think what the true benefits of wearing a helmet are.

The rest of the letter is mostly party political bleating between himself (Labour) and the Mayor (Conservative), to which I shan’t respond. As for London having an overall cycling strategy, will shall see how Andrew Gilligan, the cycling commissioner fairs during this first year in office.

Cities fit for Cycling

Posted on January 2, 2013 by jstreetley

Back in November, the excellent Julian Huppert MP and colleagues from the All Party Parliamentary Cycling Group submitted a motion to the House of Commons, entitled Get Britain Cycling. The motion supported cycling in general and particularly the Cities fit for Cycling campaign being run by the The Times.

Both the motion and The Times campaign seemed worth supporting, so I fired off a letter to my MP, the Rt. Hon. Frank Dobson, asking him to sign the motion.

My letter is reproduced below:

Dear Mr Dobson,

I am writing to draw your attention to the excellent ’Cities fit for Cycling Campaign’ run by The Times newspaper, and publicly accessible at http://www.thetimes.co.uk/tto/public/cyclesafety/, as well as Early Day Motion 679: Get Britain Cycling, proposed by Julian Huppert and others from the All Party Parliamentary Cycling Group.

Within the constituency, we are lucky to have relatively good cycling infrastructure in some places; segregated cycle paths, 20mph areas and advanced stop lines at many junctions. However, we are also home to some terrible junctions that are very difficult to navigate by bike, such as the junction between Torrington Place and Tottenham Court Road, where the cycle lane weaves from the right-hand side of traffic to the left-hand side, or much of the one-way system around Kings Cross station which has already claimed lives.

I know you are interested in issues for Central London and transport, and with that in mind, I ask you sign the EDM and support the measures contained in the ’Cities fit for Cycling’ manifesto:

Lorries entering a city centre should be required by law to fit sensors, audible turning alarms, extra mirrors and safety bars to stop cyclists being thrown under the wheels.

The 500 most dangerous road junctions must be identified, redesigned or fitted with priority traffic lights for cyclists and Trixi mirrors that allow lorry drivers to see cyclists on their near-side.

A national audit of cycling to find out how many people cycle in Britain and how cyclists are killed or injured should be held to underpin effective cycle safety.

Two per cent of the Highways Agency budget should be earmarked for next generation cycle routes, providing £100 million a year towards world-class cycling infrastructure. Each year cities should be graded on the quality of cycling provision.

The training of cyclists and drivers must improve and cycle safety should become a core part of the driving test.

20mph should become the default speed limit in residential areas where there are no cycle lanes.

Businesses should be invited to sponsor cycleways and cycling super-highways, mirroring the Barclays-backed bicycle hire scheme in London.

Every city, even those without an elected mayor, should appoint a cycling commissioner to push home reforms.

I think you will agree that these aims are both possible and sensible.

Over the Christmas holidays, I finally got a less than pleasing response, below:

Dear Mr. Streetley,

I acknowledge receipt of your letter dated 9 November about the Cities Fit for Cycling campaign. I apologise for the delay in replying.

I have already signed the Early Day Motion 679 that you refer to in your letter under the provision everyone believes that to strengthen road traffic law and its enforcement applies to cyclists jumping lights and riding on pavements.

So whilst Frank Dobson has signed the motion, it is only because he believes cyclists are part of the problem, not part of the solution to sustainable transport in London. I expected better from a man who was once the Shadow Transport Secretary and whose stated interests include Central London and transport.

Taking my bike out for a real ride

Posted on November 12, 2012 by jstreetley

Giving my bike its first real spin around Cliddesden yesterday, as part the Evans Cycles Ride it! sportive. Around 84km in 4h16, which I didn’t think was bad at all for a beginner.

Having had problems with Evans whilst I was buying the bike a few months back, I must say that the event was well organised and the staff seemed very nice, so I would recommend this series of events which tours the country. I certainly will be going to another of the ones near me.

The photo was taken by Mick Hall.