March for Science

London, Saturday April 22nd 2017

The weather is changeable as I leave the flat in the late morning. Sunny spells – dazzling my eyes clad in contact lenses – are abruptly overtaken by the English drizzle that leaves me damp and puzzled because the sun has already regained its prominence. I’m on the Westbound Piccadilly line wearing a Cancer Research UK t-shirt that reads, “I’m a researcher fighting cancer”, and I can’t tell whether I’m getting more looks than is usual on the Tube. I alight at South Kensington to meet a friend of mine, the bubbleologist Li Shen. (And yes, that is now a technical term. Li, who has a degree in mathematics, is a PhD student studying the physics of bubbles, which has far-reaching implications: from the amount of bubbles generated by different types of beer to the undesired foaming of lubricants used in oil extraction.) But we’re not just here to catch up, although it is conveniently close to his lab/office at Imperial College. No, we’re here to join the March for Science. [All of the following images were taken either by Li or by me.]

science march banner.jpg

According to the BBC, “thousands of people” joined the march, the first of its kind taking place on the annual Earth Day and organised around the world. I think the event probably got part of its boost from the Women’s Marches that took place on January 21st, the day after Donald Trump’s inauguration. Certainly, the protesters on both occasions had much in common.

destroy the patriarchy, not the planet

One of the most notable differences between the two events, however, was that this second protest was certainly smaller and also much quieter. I suppose it’s true that scientists – and yes, the marchers were mainly scientists and their relatives, partners and close friends – are a little bit shy and socially awkward. Amongst the stewards, one was trying to get the following chant off the ground, with little success, “Scientists are good at generating questions, not so good at slogans”…

french embassy

Here’s a blurry Li in the foreground, with a sharp French embassy in the background. Walking by I couldn’t help but send what’s known as a “Stoßgebet” in German to the high heavens; roughly translates as a quick (secular) prayer. For now we can breathe a brief sigh of relief after the first round of the presidential elections. Hopefully Europe, science and European Research Council funding will be able to continue to prosper.

knowledge trumps ignorance

Speaking of Trump, the March for Science event emanated from Washington DC, where it started as a protest against fake news, alternative facts and a world in which experts are regarded as worthy of derision. Honestly, as with the Women’s March, I don’t know and can’t tell how much impact marches like these actually have in politics, but as a start there was significant media coverage. Even Buzzfeed compiled its list of top banners and slogans (some scientists do have a sense of humour). My personal favourite was this one, of course.

big brains

I do know that within three months I went to two marches, the first two of my life. Ideally, I won’t have to go to any more and will be able to spend my Saturdays in the lab, where a diligent PhD student should be (and where I know some of my colleagues were). Lastly, let’s give reason, described by Wikipedia as being “the capacity for consciously making sense of things, applying logic, establishing and verifying facts, and changing or justifying practices, institutions, and beliefs based on new or existing information”, a big thumbs up.

reason

Behrens lab retreat 2016

Imagine spending a weekend in these idyllic surroundings in the Peak District with nothing to do but talk about and discuss science.

image1-1

The Peak Mermaid Inn – taken at sunrise on November 13th 2016

Well, that’s exactly what we, the Behrens lab, did last weekend. We invited a keynote speaker, Roland Rad, and Dieter Saur’s group from the Technical University of Munich to join us. Each of us gave a talk about the most interesting or exciting aspects of our projects and in between we drank copious amounts of coffee. In the evenings we cooked enough food to feed a small regiment, drank beer, played pool, darts or table football, all punctuated by heated debates about science. Although this wasn’t a relaxing weekend by normal standards, it was motivating and inspiring and a good reminder of why I enjoy being a scientist: a combination of rational and logical thinking, curiosity and the drive to learn new things for their own sake, all shared with people who, by and large, know more than I do and think differently.

Of the talks I just want to highlight one in particular, because my project also uses one of the techniques mentioned. Dieter Saur is a medical doctor and has his own lab group, which studies mainly gastrointestinal diseases, including pancreatic cancer. In a recently published paper (Schönhuber et al, 2014) they describe an experimental system in mice called the “dual recombinase system“. This is a genetic system that allows the study of complex diseases such as cancer. Until recently it was only possible to simultaneously switch on a gene that drives tumour progression and switch off a gene that prevents tumour formation in a cell type or organ of interest (e.g. in the pancreas). Using the dual recombinase system it is possible to make genetic alterations sequentially. For example, in the beginning of a mouse’s development one can activate a potent tumour driver called Ras and delete an important tumour suppressor called p53. And then, once a tumour has formed, one can additionally delete genes that may be important to maintain the established tumour. Alternatively, the dual system also makes it possible to make genetic changes to the normal cells surrounding the (pancreatic) tumour. If all goes well then I will be able to use these tools to conduct experiments like this in the next year or so.

15044797_10154563370871405_2126581266_o zip-line

Oh and admittedly we did have an activity scheduled that was slightly less scientific: we got all geared up and went on a GoApe outing. Secured by a harness and after some rigorous safety instructions we got to fly down zip lines, balance over gaping abysses and jump over the void below.


Lastly, the following week saw Queen Mary University London and Barts host the 11th UK cancer stem cell symposium. There were several interesting talks, including by group leaders at the Crick Institute, but the most unusual talk was given by a philosopher called Lucie Laplane. She did her PhD in philosophy and combined this with a research master’s in stem cell biology. Putting the two fields together she came up with a classification of (cancer) stem cells using definitions and guidelines borrowed from philosophy, applied to biology. [In general, researchers agree that stem cells are cells that can self-renew (i.e. generate new copies of themselves) and can produce differentiated/specialised daughter cells.] The most important point was how to pin down what kind of characteristic “stemness” is or what makes a stem cell a stem cell:

csc-table

Framework for defining (cancer) stem cells – copied from Lucie Laplane’s talk at the symposium

For instance, in some cases a stem cell might always be a stem cell no matter what the environment is like (i.e. categorical); other stem cells may be dispositional in nature, meaning that they always have the potential to act as a stem cell but only do so in a permissive environment. Alternatively, being a stem cell might not be property of a single cell at all but rather an attribute of an entire organ (i.e. systemic). Laplane argued that the way we define (cancer) stem cells has a huge impact on how we try to treat diseases such as cancer. For example, if cancer stem cells are “systemic” then even the best therapies targeted against these cells will fail because the system/the tumour will make new cancer stem cells from other tumour cells. Hans Clevers, one of the Gods in the stem cell field, wrote a glowing review of the book here.

References:

Laplane, Lucie. Cancer Stem Cells: Philosophy and Therapies. Harvard University Press, 2016.

Schonhuber N, Seidler B, Schuck K, Veltkamp C, Schachtler C, Zukowska M, Eser S, Feyerabend TB, Paul MC, Eser P, Klein S, Lowy AM, Banerjee R, Yang F, Lee C-L, Moding EJ, Kirsch DG, Scheideler A, Alessi DR, Varela I, Bradley A, Kind A, Schnieke AE, Rodewald H-R, Rad R, Schmid RM, Schneider G, Saur D (2014) A next-generation dual-recombinase system for time- and host-specific targeting of pancreatic cancer. Nat Med 20: 1340-1347

The #IceBucketChallenge Two Years On

August two years ago saw our facebook feeds flooded with footage of friends and acquaintances dousing themselves in ice-cold water to raise awareness and money for amyotrophic lateral sclerosis (ALS; or motor neuron disease (MND)) charities. It was the topic of the inaugural blog post and a follow-up one year later. My inherently slightly cynical and skeptical nature questioned whether all this social media craze (and £87.7 million raised) would actually make a difference. Well, facebook came to the rescue and linked me to articles from the BBC and The Guardian alerting me to a paper published recently in Nature Genetics (Kenna et al., 2016).

The researchers contributing to this study work in eleven countries across the world. (Who ever thought science benefited from international collaboration? Am I still frustrated by Brexit? No, not at all…) Large proportions of the funding were provided by the National Institute of Health in the USA as well as  ALS and MND Associations in the USA and UK. Kenna et al. sequenced those parts of the genome that are actively expressed – a technique known as whole exome sequencing – in over 1000 familial/inherited ALS patients and over 7000 controls. Since sequencing technologies are becoming better and cheaper all the time, this is the less impressive part of the study. Next, all this data was processed using so-called gene burden analyses. This is where I stop understanding what is done with the data, but in essence it was possible to use previously known genetic risk factors of ALS to infer overlooked genes that are also associated with the disease. In the figure below the genes indicated in blue are genes that were already known to confer ALS risk (e.g. SOD1 and FUS), whereas those in black are the new genes, and everything above the red dotted line was considered statistically significant.

NEK1

Graph depicting genes associated with ALS risk – copied directly from Kenna et al., 2016

As you can see, the researchers identified mutations in the NEK1 gene through these sequencing and data analysis experiments. However, only about 10% of people with ALS have the familial/inherited form of the disease. Therefore Kenna et al. then went on to check whether these NEK1 mutations could also be found in samples from patients with sporadic ALS and indeed they could. Overall approximately 3% of ALS patients have abnormal NEK1 genes.

After all this data analysis the paper ends with a description of what the NEK1 protein normally does and what it might not be doing in ALS patients’ cells: NEK1 helps to repair damaged DNA and contributes to the formation of an organelle called the cilium. Now future experiments will have to focus on exactly why and how mutations in NEK1 contribute to ALS. And since only 3% of ALS patients have NEK1 mutations there are still many other genes to discover.

The Project MinE aims to do just that – with headquarters in the Netherlands, this collaborative DNA sequencing project is analysing samples from even more ALS patients and controls. Their website says that a donation of €75 enables sequencing and analysis of a single chromosome! Anyone fancy another cold shower?

Lastly, I’ve found an interesting article combining two of my favourite things (science and Impressionist art) – so look forward to that in the next post.

Reference:

Kenna KP, van Doormaal PTC, Dekker AM, Ticozzi N, Kenna BJ, Diekstra FP, van Rheenen W, van Eijk KR, Jones AR, Keagle P, Shatunov A, Sproviero W, Smith BN, van Es MA, Topp SD, Kenna A, Miller JW, Fallini C, Tiloca C, McLaughlin RL et al. (2016) NEK1 variants confer susceptibility to amyotrophic lateral sclerosis. Nature Genetics advance online publication.

Cancer Research UK – PhD Student Meeting

Cancer Research UK (CRUK) is the world’s largest independent cancer charity (according to Wikipedia)  and funds thousands of scientists across the UK. In the latest annual report they state that more than £340 million were spent on research. Take a look at the fancy infographic here to see a break-down of how that money was spent:

annual report

The reason for writing this post on CRUK is that today the charity held its first-ever first year PhD students’ meeting in London, at the Quaker Friends House near Euston station. The attendees came from all over the UK: from as far afield as Aberdeen and Manchester to Oxford and Cambridge and finally us lazy Londoners who could afford to get up later than on a normal lab day.

The main aims of the meeting were to get to know some of the people working at CRUK’s head office in London and how, in future, we might apply for their funding. One of the first things I learnt today was that CRUK has made four cancer types – brain, lung, pancreatic (!) and oesophageal – “strategic priorities”, because the survival rates for these are still low and lagging behind those of, say, breast and prostate cancer. We also heard, from the senior research funding manager, Richard Oakley, how CRUK spends its money and what we can and are meant to do to help. Among other things this involves wearing branded t-shirts and participating in fundraising events. So tomorrow morning I will wear this to run in the park in preparation for the 10 km Race for Life happening at the end of June – please feel free to fund me and/or the maybe pink team and/or join the run! [We can start a separate conversation on the topic of the martial language used by CRUK, and other charities, to help raise the money. N.B. The back of the t-shirt reads, “Ask me about my life-saving research.”]

cruk

Since doing a PhD is all about the learning experience, most of the morning was filled with one of three workshops on either a) assertiveness, b) time management, or c) having an effective working relationship with your supervisor. I chose the first option, and although some people (especially in my lab) will argue that it would be better if I were a bit more quiet on occasion, I thought it would be interesting to see what it could offer. The basic message was, of course, quite clear: effectively communicate your needs whilst appreciating other people’s needs. Easier said than done for sure. The only thing that helps is practising being in potentially awkward situations and putting oneself outside one’s comfort zone, which is where learning can happen. Possibly the most helpful information was to realise what isn’t assertive behaviour (e.g. being too passive, or too (indirectly) aggressive) and making sure to recognise those behaviours in oneself and learning to avoid them in future. We’ll see how that goes.

Over lunch we got to browse a few posters. I particularly enjoyed the ones on intestinal stem cells and a potential preventative treatment for breast cancer using the diabetes drug Metformin. And lastly, we were politely, with the help of beer and/or wine, coerced into networking…

Synthetic biology

What I cannot create, I do not understand. – Richard Feynman

[Disclaimer: I am an amateur when it comes to synthetic biology, so if you spot mistakes in terminology or just sloppy expressions then please feel free to correct me.]

Synthetic biology is a topic that is being mentioned more and more frequently in scientific, but also mainstream, news. As with many things in life there is no one single, clean definition of this field of study. Broadly speaking, synthetic biology can either mean using existing building blocks (e.g. components of an organism’s DNA such as regulatory sequences or protein-coding sequences) to create new combinations, or to make up completely new biological building blocks (see, for example, the Editorial in Nature Methods, 2014 and a Q&A-style paper by Church et al., 2014).

Recently, a paper published in Science (Hutchison et al., 2016) made headlines: Craig Venter and his research team (or should I call it an army?) created the first fully synthetic cell. That is, they designed its genome, artificially synthesised its DNA and then transplanted it into existing cells, which subsequently lost their own genetic information, thus creating an entirely new type of cell. The cells were imaginatively called “JCVI-syn3.0” and look like this by scanning electron microscopy:

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JCVI-syn3.0 (scale bar: 0.2 µm) – image copied directly from Hutchison et al., 2016

Ignoring the fact that these cells were created almost entirely from scratch (the DNA did go into existing cells that already had a membrane etc.) in a Herculean effort, one of the interesting features of their genomes is that 17% of their genes have an unknown function. The cells have a minimal genome comprising 473 genes of which 83% can be classified into one of the following four functional groups: expression of genome information, preservation of genome information, cell membrane and cytosolic metabolism. So we do not even fully understand these simplest of all cells. This is in stark contrast to the (earlier) studies on bacteriophages (viruses that infect bacteria): here the so-called lambda phage is a good example of us understanding what each element of its genome does. An accessible account of how it works is given in Mark Ptashne’s 1986 book “A Genetic Switch”, which also, in some ways, paved the way for synthetic biology since it describes how knowledge of gene regulatory networks could be one day exploited to build new networks.

This means that Richard Feynman’s quote above does not hold completely true in the realm of synthetic biology. Funnily enough, when Venter & Co. first built semi-synthetic cells (Gibson et al., 2010) they used the four DNA codons (A, T, C, G) to incorporate small messages, the names of the authors of the paper and some quotes, including Feynman’s. However, according to this article in The Scientist they misquoted him as having written, “What I cannot build, I cannot understand.”

The example of JCVI-syn3.0 falls into the category of building something new from existing building blocks (genetic elements). However, other researchers are trying to expand the way cells work. For example, in a proof-of-principle paper Neumann et al., 2010 showed that they could expand the way ribosomes decode the famous genetic code. Normally, DNA in the form of messenger RNA is decoded in triplets (e.g. AUG represents a common start codon, which is translated into the amino acid methionine). Neumann et al. forced the evolution of a ribosome that can read the nucleotides in quadruplets. At the same time they managed to make these ribosomes translate the new codons into unnatural amino acids. This sort of approach may allow for the production of completely new proteins and molecules, which may, for example, have therapeutic applications. In fact, this has already been partially achieved for the anti-malarial drug artemisinin (see Paddon & Keasling, 2014 for a review).

Lastly, I would just like to add that part of my inspiration to read and write on the topic of synthetic biology came from a fellow PhD student, Aakriti Jain.  Until recently, Aakriti was an editor of the PLoS synthetic biology community, which aims to bring together scientists from different fields and allows them to communicate their research to a wider audience.

References:

Church GM, Elowitz MB, Smolke CD, Voigt CA, Weiss R (2014) Realizing the potential of synthetic biology. Nat Rev Mol Cell Biol 15: 289-294

Editorial (2014) Synthetic biology: back to the basics. Nature Methods 11: 463-463

Gibson DG, Glass JI, Lartigue C, Noskov VN, Chuang R-Y, Algire MA, Benders GA, Montague MG, Ma L, Moodie MM, Merryman C, Vashee S, Krishnakumar R, Assad-Garcia N, Andrews-Pfannkoch C, Denisova EA, Young L, Qi Z-Q, Segall-Shapiro TH, Calvey CH et al. (2010) Creation of a Bacterial Cell Controlled by a Chemically Synthesized Genome. Science 329: 52-56

Hutchison CA, III, Chuang R-Y, Noskov VN, Assad-Garcia N, Deerinck TJ, Ellisman MH, Gill J, Kannan K, Karas BJ, Ma L, Pelletier JF, Qi Z-Q, Richter RA, Strychalski EA, Sun L, Suzuki Y, Tsvetanova B, Wise KS, Smith HO, Glass JI et al. (2016) Design and synthesis of a minimal bacterial genome. Science 351: 1414-U73

Neumann H, Wang K, Davis L, Garcia-Alai M, Chin JW (2010) Encoding multiple unnatural amino acids via evolution of a quadruplet-decoding ribosome. Nature 464: 441-444

Paddon CJ, Keasling JD (2014) Semi-synthetic artemisinin: a model for the use of synthetic biology in pharmaceutical development. Nat Rev Micro 12: 355-367