A Fledgling PhD Student

Here I am standing in front of the gigantic Francis Crick Institute in London, which is situated right next to St. Pancras railway station and just behind the British Library. I’m not actually saluting, just shielding my eyes from the sun. [Photo courtesy: Kai Wang]

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As you can see, even a wide-angle lens cannot quite capture all of the building in a single shot. A recent News article in Nature described the institute as “Sir Paul’s Cathedral”. It will be the biggest biomedical research centre in Europe – it’s bigger than Buckingham Palace – and will become populated with scientists early next year. The building costs came to a whopping £700 million. Additionally, its annual budget will be £150 million, which is more than the School of Biological Sciences at the University of Cambridge received in the academic year 2013/14 according to this report (if I am interpreting it correctly). The charity Cancer Research UK (CRUK) is one of the Crick’s main funders and this summer they are launching an art campaign to raise money for the Crick: CRUK is setting up 21 DNA sculptures across London so that you can go on a DNAtrail and at the end of the exhibit the “sculptures will be auctioned in September 2015 to raise funds to help complete the construction of the Francis Crick Institute”. Makes it sound slightly like they won’t be able to complete the building unless the auction goes really well… As far as I’m aware the Crick already has a roof and is currently being furnished. [Picture copied from the CRUK website.]

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Sir Paul Nurse’s “Crick project” was/is daring and the numbers above are certainly impressive. But with this grandeur come great expectations. Sceptics of the project will be awaiting great results, results even better (and by that I probably mean more translatable into medicine and the real world) than those already being produced by the research groups moving into the Crick. Although I have no doubt that it will be an exciting place to work, with excellent facilities and support staff, I can imagine it will also be a high pressure environment. We shall see.

At the moment it’s barely been a week since I graduated with my undergraduate degree (woohoooo!) and part of my brain is already getting a little bit impatient for something new to think about and to work on. Another, perhaps more calculating, part of my brain is saying, “Are you mad? Enjoy these weeks of freedom. You’ll never have holidays like these again!” In any case, the PhD doesn’t start until September but in the mean time I’m scheduled to join a lab meeting of my future lab in late July. That means that I should do a bit of preparatory reading beforehand, including the lab’s most recent publications (see below).

References:

Behrens A, van Deursen JM, Rudolph KL, Schumacher B (2014) Impact of genomic damage and ageing on stem cell function. Nature Cell Biology 16: 201-207

Chakraborty A, Diefenbacher ME, Mylona A, Kassel O, Behrens A (2015) The E3 ubiquitin ligase Trim7 mediates c-Jun/AP-1 activation by Ras signalling. Nat Commun 6: 6782

Diefenbacher ME, Chakraborty A, Blake SM, Mitter R, Popov N, Eilers M, Behrens A (2015) Usp28 Counteracts Fbw7 in Intestinal Homeostasis and Cancer. Cancer Research 75: 1181-1186

Sancho R, Gruber R, Gu G, Behrens A (2014) Loss of Fbw7 reprograms adult pancreatic ductal cells into alpha, delta, and beta cells. Cell Stem Cell 15: 139-153

Sancho R, Cremona CA, Behrens A (2015) Stem cell and progenitor fate in the mammalian intestine: Notch and lateral inhibition in homeostasis and disease. EMBO Reports 16: 571-581

Schulein-Volk C, Wolf E, Zhu J, Xu W, Taranets L, Hellmann A, Janicke LA, Diefenbacher ME, Behrens A, Eilers M, Popov N (2014) Dual regulation of Fbw7 function and oncogenic transformation by Usp28. Cell Rep 9: 1099-1109

CRISPR Digest #6

Exams are over and the real, adult world is about to begin. My first taste of it has come in the form of flat hunting in London and let me tell you that this is, in many ways, more stressful than sitting exams. In any case, I thought I would have far more time to read and write after term finished but I was clearly wrong. So here is just a brief CRISPR update, including some recent reviews.

Firstly, in response to the paper earlier this year (Liang et al, 2015), which reported the first use of CRISRP/Cas9 genome-editing in human embryos, several influential members of the scientific community, including Emmanuelle Charpentier, Jennifer Doudna and Craig Venter (the first to sequence a human genome using the “shotgun” sequencing method), have commented on this development. When asked whether they thought human germline engineering was inevitable, Venter, for example, answered that he was convinced it would happen and would be difficult, if not impossible, to control. Charpentier and Doudna, on the other hand, were careful to reiterate that there are considerable risks, including ethical issues, that need to be dealt with before undertaking such experiments. In particular, Doudna and her colleagues argue that off-target effects still occur at non-insignificant rates and that even successful gene-editing could lead to unexpected effects due to genetic interactions with other, normal DNA variations in a human’s genome. Lastly, reference is made to the 1975 conference on recombinant DNA held in Asilomar (California) at which scientists decided that for 16 months work using recombinant DNA would be put on hold so that stricter, international guidelines could be implemented. Would such a “moratorium” (Baltimore et al, 2015) be applicable to CRISPR/Cas9 human genome-editing too?

Secondly, a new CRISPR review (Sternberg & Doudna, 2015) was published in Molecular Cell last month. It includes some of the latest research articles and another one of these handy overview spider diagrams:

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Lastly, a new review (for which I can’t yet find the full online reference; Mou et al Genome Medicine (2015) 7:53) discusses CRISPR/Cas9 in the context of generating mouse models of cancer. Since CRISPR can be used to specifically alter single DNA bases, cause chromosomal translocations or completely knock-out gene function one can use the system to mimic the mutations that are normally acquired during tumourigenesis. For example, by using mice which inducibly express the Cas9 nuclease one can then provide the guide RNAs by injecting them directly into mouse livers to initiate cancer formation. Alternatively, groups have manipulated haematopoietic stem cells ex vivo using CRISPR and then re-introduced these cells into mice to model certain leukaemias such as acute myeloid leukaemia. Who knows, maybe I’ll even be using one of these models during my PhD on pancreatic cancer, starting in September?

References:

Baltimore D, Berg P, Botchan M, Carroll D, Charo RA, Church G, Corn JE, Daley GQ, Doudna JA, Fenner M, Greely HT, Jinek M, Martin GS, Penhoet E, Puck J, Sternberg SH, Weissman JS, Yamamoto KR (2015) Biotechnology. A prudent path forward for genomic engineering and germline gene modification. Science 348: 36-38

Bosley KS, Botchan M, Bredenoord AL, Carroll D, Charo RA, Charpentier E, Cohen R, Corn J, Doudna J, Feng G, Greely HT, Isasi R, Ji W, Kim J-S, Knoppers B, Lanphier E, Li J, Lovell-Badge R, Martin GS, Moreno J, Naldini L, Pera M, Perry ACF, Venter JC, Zhang F, Zhou Q (2015) CRISPR germline engineering – the community speaks. Nat Biotech 33: 478-486

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

Sternberg Samuel H, Doudna Jennifer A (2015) Expanding the Biologist’s Toolkit with CRISPR-Cas9. Molecular Cell 58: 568-574