Springer Nature work experience

In the stories we tell ourselves about our lives, life is usually linear. And if that’s true, and at least for simplicity’s sake let’s assume it is, then I’ve been linearly doused in good fortune, which I’ve supplemented with a sprinkling of common sense. The story starts, as we all know, with the fusion of two cells becoming one, but because this is a blog and not my memoirs, I’ll start in the summer of 2014, when my body numbered dozens of trillions of cells.

I was doing an undergraduate research programme at Cold Spring Harbor Laboratory where I was introduced, for the first time, to career opportunities outside academia. It was, in the beginning, a faint knocking at the door of my consciousness and gradually, by the end of the summer, a migraine of future possibilities: scientific editing and publishing. That’s when I started my blog and a year later began working for eLife. Next thing I knew I was doing a PhD at the Francis Crick Institute. Then it turned out that the PhD programme offers third-year students the opportunity of a work placement in a science-related field.

So the obvious questions were: would I be suited to becoming an editor? Would I enjoy the job? And the answers might lie only several rail tracks across from the Crick, at Springer Nature, on the other side of King’s Cross/St. Pancras.

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I spent (only) one week with the cancer team at Nature Communications, the “open access, multidisciplinary journal dedicated to publishing high-quality research in all areas of the biological, physical, chemical and Earth sciences. Papers published by the journal aim to represent important advances of significance to specialists within each field.”

My main aim, slightly less ambitious maybe, was to find out what a scientific editor does, exactly. All the team members were generous with their time and I got to participate in daily life: I read and assessed the novelty of freshly submitted manuscripts; I collated and integrated reports from reviewers to form a basis for a decision to the authors; I saw what happens when a paper gets accepted (a lot of copy editing and admin); and I attended a couple of team meetings where the editors discussed particularly tricky manuscripts. I loved most about these activities that, at the heart of it all, was always the science, and that there was always something new to read and learn and critically assess.

In addition to “normal scientific editors”, there are also reviews editors. This species of editor commissions reviews from experts in a given field, chases them to actually do the writing and then, often extensively, edits the review.

I also got the chance to speak to the publishers of the Nature research journals. Broadly speaking they need to make sure that the journals operate according to viable business models, but also steer the overall direction of the journals. For example, only this year Springer Nature launched several new journals, including Communications Biology and Communications Physics, which will fill the gap between Nature Communications and Scientific Reports, a journal that requires findings to be technically sounds but not necessarily novel. Publishers also build new platforms to collate, for example, research related to cancer into a new collection, or contextualise content related to the sustainable development goals.

A single week can never be a true representation of life as an editor, especially because I got to talk to so many different people and gain a glimpse into several parts of the whole company. So I’d like to say thank you to everyone for taking the time to talk to me and answer my questions!

Lastly, if this (also) sounds like your dream job, then why not sign up to the “talent pool” and upload your CV and cover letter?

 

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The halfway mark

A few days ago someone called me a “senior PhD student”. And I know it’s true. I’m just over two years, or halfway, through the official funding length of my PhD. “Official” because a lot of students in my lab end up staying for longer to publish a paper, or sometimes two. So I thought it would be a good time to take stock, take a moment to re-evaluate my life choices while trying not to fall into that abyss labelled “existential crisis”.

First, let me say this: doing a PhD is hard. Harder than you imagine it will be, even after countless people have told you that it will be challenging or difficult. It’s hard in ways I hadn’t foreseen. It tries my patience – with people, with inanimate objects, with biology itself – on a daily basis. It makes me do tasks I don’t particularly enjoy (e.g. repetitive pipetting) but that need to be done in order to accomplish those I do. (I realise that this applies to a lot of different jobs.) At the same time, especially on an intellectual level, I find it less challenging, less stimulating than I had expected or hoped for. A lot of time and energy are used to concentrate on practicalities, which leaves less of the brain’s random access memory for really thinking about science.

But it’s not only frustrating, not only bad. I have learnt a lot in the last two years. Practical skills in the lab, of course, including how to clean up centrifuges after almost breaking them, how to plan and execute experiments that take days if not weeks to complete, how to always set up experiments whose results can neatly be presented in figures, including using all the proper controls. Doing a PhD is also teaching me how to deal with the feeling of not having finished or completed something (the work never ends) as well as juggling the (natural?) highs and lows, the alternating sensations of shining confidence and utter dejection, that accompany work. [I’m pretty sure the levels of emotion elicited by work are more extreme than those caused by hormones.] Oh and then of course all the new theoretical knowledge in the forms of attending talks and conferences, as well as reading papers. Isn’t it pretty cool, for example, that using a modified version of CRISPR/Cas9 it’s now possible to precisely edit certain DNA base pairs (rather than making a cut in the DNA and hoping for the best; Gaudelli et al, 2017)? Or that reading about cancer stem cells during my degree has turned into me actually doing some of those types experiments?

Another thing that takes getting used to is that progress is slow. Improvement and success can’t simply be measured by essay feedback and exam results. It takes more effort to see and appreciate how far we, as PhD students, have come from our even humbler beginnings as school and university students. As proof of this let me show you the evolution of a scientist:

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Above: At the summer science camp of the Vienna Open Lab; Below: As a PhD student at The Francis Crick Institute

In addition to acquiring a better haircut I’ve also increased my skills when it comes to processing and taking immunofluorescence images on a fancy microscope. The Zeiss software installed on our microscopes is called Zen, which is ironic when I lose my cool after it crashes repeatedly. (The software we use to acquire data on our flow cytometers is called Diva, which is much more apt.)

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Above: a mouse embryonic fibroblast, taken with lots of help at the MFPL in Vienna; Below: Zen screenshot of mouse pancreatic cancer tissue, taken at The Crick

The halfway mark also coincides with considerable change in our lab: several senior PhD students and post-docs are leaving for other positions (academic or as MBA students) and there are two new PhD students, one of whom is also a clinical fellow (who happens to read the London Review of Books!). This makes me one of the more seasoned members of the lab and I think it’s a good opportunity to make sure I take more responsibility, try to be more innovative, as well as being generous with my time to help others, as others were when I started.

There are several things I will focus on in the near future to make sure I don’t lose motivation: attending more conferences (such as the international PhD student cancer conference in Berlin earlier this year); focussing on one avenue of my research project more and more, really going to the depth of one small problem; going to more lectures; making more time to think; reminding myself regularly of the progress I’ve already made.


References:

Gaudelli NM, Komor AC, Rees HA, Packer MS, Badran AH, Bryson DI, Liu DR (2017) Programmable base editing of A•T to G•C in genomic DNA without DNA cleavage. Nature advance online publication

CRISPR Digest #14

Two years ago, in spring 2015, Liang et al. published the first report of gene-editing in human embryos using CRISPR/Cas9 (mentioned previously here, here and here). At the time no high-profile journal was willing to take on the risk of publishing what was perceived to be a controversial study. Liang et al. were trying to correct mutations in the human beta-globin gene – mutations in this gene can lead to a group of diseases called beta thalassaemias, including sickle cell anaemia – in human embryos that had been fertilised by two sperm cells (and could therefore never develop). In fact, the take-home message from their study was that using the techniques available to them at the time led to a host of unwanted side effects, including the creation of mutations at other sites in the embryo genome and the “correction” of the beta-globin gene with a similar gene called delta-globin.

Last month, a different group (Ma et al. – four first authors and five corresponding authors!) published more work on human embryo CRISPR/Cas9 gene-editing, this time in Nature. Like Liang et al. this paper also tried to tackle a monogenic disease, a disease that is caused by a well-defined mutation in a single gene, called hypertrophic cardiomyopathy. The affected gene is MYBPC3 and when mutated (denoted as DeltaGAGT in the figure below) this leads to a thickening of the heart muscle, which in turn can cause heart failure. The authors used donor sperm with the MYBPC3 mutation together with healthy oocytes to perform their experiments. In the first approach the eggs were fertilised by the sperm and only subsequently, during S phase, were the guide RNA, Cas9 protein and a piece of non-mutated donor DNA injected. The guide RNA was designed to specifically recognise the mutant version of MYBPC3, which recruits the Cas9 protein to make a cut in the DNA, and then the donor DNA would serve as a template to repair the sperm’s mutated gene. Ma et al. observed that this technique worked but often generated so-called mosaic embryos, which contained a mixture of healthy and mutated cells. This incomplete gene correction happened because during S phase both the maternal and paternal chromosomes duplicate and therefore the CRISPR/Cas9 system would have to correct two mutated MYBPC3 genes before the first cell division.

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Schematic depicting CRISPR/Cas9 stage at zygote stage (top) versus together with sperm (bottom) – copied directly from Ma et al, 2017

In a second approach, Ma et al. wanted to overcome this mosaicism by injecting the CRISPR components together with the sperm during the M phase of the oocyte. Now only one copy of mutant MYBPC3 had to be corrected and this succeeded in producing completely healthy embryos. Ma et al. also checked to make sure that these embryos did not carry any unwanted, off-target mutations.

Last but not least, Ma et al. provided evidence that often the human zygote used the healthy maternal gene to provide a template for the repair of the mutated paternal gene, instead of the injected DNA template. This is significant because in most cell types the DNA double-strand breaks caused by Cas9 are usually repaired in an imprecise manner (called non-homologous end joining) and lead to further mutations. Ma et al. therefore argued that “human gametes and embryos employ a different DNA damage response system”.

This finding could be of huge importance, both to the basic understanding of human embryonic development as well as to potential therapeutic CRISPR/Cas9 applications. However, four days after the Nature paper was published online, several prominent scientists posted a riposte on the pre-print server bioRxiv. Egli et al. criticised the first paper quite heavily by raising theoretical objections/concerns; they couldn’t have tried to replicate the experiments in such a short time frame. [Note that this pre-print was, of course, not peer-reviewed, although the authors have confirmed that they were trying to get their work published in Nature as well.]

Among other more technical issues to do with the way in which healthy and mutant genes were detected, Egli et al. pointed out that after fertilisation the maternal and paternal chromosomes remain physically separated (indicated by the arrows in the figure below) until just before the first cell division. Therefore, Egli et al. argued, it is highly unlikely that the healthy maternal MYBPC3 gene could serve as a template for the repair of the mutant paternal gene. This strikes me as a strong argument, not being at all familiar with early human development. Overall, Egli et al. suggested that Ma et al. were simply not detecting the mutant gene in their embryos but not providing good enough evidence of a corrected gene. The scientific debate will, no doubt, continue and I think having bioRxiv as such a rapid place for the exchange of ideas can drive scientific discourse.

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Pictures of a human zygote (fertilised egg/oocyte) and its very early development – copied directly from Egli et al, 2017

Since this is a digest it should also contain some other relevant CRISPR/Cas9-related news. One of the post docs I met at Cold Spring Harbor Laboratory in 2014, Serif Senturk, published a paper early this year in which the authors show how they can switch CRISPR on or off in living cells. They did this by fusing the Cas9 protein to another, destabilising protein domain, which caused the attached Cas9 to get degraded. However, when a “shield molecule” was added to the cells, the destabilising domain was no longer active and the Cas9 could accumulate. This innovation counteracts the problem of off-target effects, which are often due to the long duration that Cas9 is active for. Pretty neat system, I think.

Senturk 2017

Schematic depicting Cas9 fused to a destabilising domain – copied directly from Senturk et al, 2017


References:

Egli D, Zuccaro M, Kosicki M, Church G, Bradley A, Jasin M (2017) Inter-homologue repair in fertilized human eggs?
bioRxiv: http://www.biorxiv.org/content/early/2017/08/28/181255

Liang P, Xu Y, Zhang X, Ding C, Huang R, Zhang Z, Lv J, Xie X, Chen Y, Li Y, Sun Y, Bai Y, Songyang Z, Ma W, Zhou C, Huang J (2015) CRISPR/Cas9-mediated gene editing in human tripronuclear zygotes. Protein Cell: 1-10

Ma H, Marti-Gutierrez N, Park SW, Wu J, Lee Y, Suzuki K, Koski A, Ji D, Hayama T, Ahmed R, Darby H, Van Dyken C, Li Y, Kang E, Park AR, Kim D, Kim ST, Gong J, Gu Y, Xu X et al. (2017) Correction of a pathogenic gene mutation in human embryos. Nature 548: 413-419

Senturk S, Shirole NH, Nowak DG, Corbo V, Pal D, Vaughan A, Tuveson DA, Trotman LC, Kinney JB, Sordella R (2017) Rapid and tunable method to temporally control gene editing based on conditional Cas9 stabilization. Nature Communications 8: 14370

PhD – 21 months in 

Do you remember my optimistic blog post about finding my bearings in the lab after a month of the PhD? I also included pictures of a failed western blot and slightly crushed centrifuge tubes.

Well, twenty months later and I’m still making mistakes. Often they’re new and different mistakes, which could almost be exciting. But today I made the same mistake and lost a lot of plasmid-growing bacteria (bacteria I am using as work horses to produce specific DNA for me) in a centrifuge (which I subsequently cleaned!)…

Photographic evidence attached.

11th International PhD Student Cancer Conference

A glorious three day bonanza of beer, brains and BRAF. — Tom Mortimer, PhD student at The Francis Crick Institute

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On Wednesday morning, June 14th, twenty PhD students from The Francis Crick Institute woke up early and made their way from one of London’s five airports to Berlin. Specifically to Campus Berlin-Buch – the geographic equivalent of Clare Hall Laboratories, situated right next to the M25, the London Orbital Motorway, 25 kilometres from the city centre – home to the Max Delbrück Center for Molecular Medicine (MDC).

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On the campus of the MDC

We were attending the 11th international PhD student cancer conference (IPSCC), which was initiated at the London Research Institute (LRI), one of the founding partners of The Crick. In fact, the opening remarks were held by Holger Gerhardt, a former group leader at the LRI. He immediately gave the meeting a political flavour by stressing how important diversity is within research, openly showing his disdain for Brexit.

The conference was organised by PhD students at the MDC for other students studying cancer across Europe, with delegates from the UK, Germany, Italy and the Netherlands. The talks were spread over three days and the topics ranged from in silico computational biology and large-scale genomics approaches to cell signalling and in vivo cancer metabolism. Strikingly, when speakers were given suggestions or asked questions they seemed sincere in their responses, especially when they didn’t know the answers. One of the talks most out of the ordinary was given by Joseph Hodgson from the CRUK Beatson Institute in Glasgow: he uses fruit flies to study the process of weight loss and muscle wasting due to cancer (also known as cachexia).

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Joseph Hodgson showing fluorescent images of fruit fly muscle wasting (right)

The prize for the best talk went to Rajbir Nath Batra, from the CRUK Cambridge Institute, who studies DNA methylation dynamics in breast cancer in Carlos Caldas’ group. The best poster by far was created by Cora Olpe, also at the Cambridge Institute, who is trying to understand the chemopreventive effect of aspirin on colorectal cancer in the group of Douglas Winton.

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Cora Olpe’s poster made use of Aspirin’s chemical formula to great effect

On the social side of things, conversation was enabled by providing generous amounts of delicious German beer as well as having us participate in career workshops, including on grant writing, conducting clinical trials, science communication and on becoming an entrepreneur. All in all it was great to get the opportunity of meeting the people who might be our future collaborators.

The keynote speakers were Mónica Bettencourt-Dias (Gulbenkian Institute, Lisbon) and Madalena Tarsounas (Institute for Radiation Oncology, Oxford). Lastly, Klaus Rajewsky (MDC, Berlin), a world-renowned immunologist, gave a lecture on his “life in science”. He ended the conference also on a political note, juxtaposing the 1975 referendum on the UK’s membership to the European common market with the Brexit referendum, also stressing how important international collaboration and diversity are within science.

Next year the 12th IPSCC will be hosted by The Francis Crick Institute. We hope to have a great turnout (especially in the face of Brexit) – see you there!