Not all cancer cells are equal

This is the essay I submitted to the Max Perutz Writing Award 2016.

Look at yourself in the nearest mirror and, if you aren’t too squeamish, visualise the inside of your body. It’s obvious that not all your cells are the same. We are made of many different tissues that perform different tasks: skin cells protect us from the environment, white blood cells defend us against infections, nerve cells allow us to move and think. Cancer – the uncontrolled growth of cells – can arise from virtually any type of tissue. We hear about new treatments for skin cancers, about raising money for childhood leukaemias, about inoperable brain tumours. We know that there are different types of cancer.

But an individual tumour in a tissue is also complex. Researchers realised decades ago that, like our healthy bodies, tumours aren’t simply lumps of identical cells; that within each tumour there are different cell types. For instance, some tumour cells divide indefinitely to keep the cancer alive, others invade into surrounding tissue and spread to other sites of the body, while yet others stimulate blood vessels to grow. Some cancer cells even combine several of these properties.

In our laboratory we study the pancreas, an organ of the digestive system, which aids digestion and controls metabolism throughout the body by secreting hormones such as insulin. In particular, we investigate variations among cell types in the most common kind of pancreatic cancer called pancreatic ductal adenocarcinoma (PDAC for short). PDACs are among the most deadly cancers with only about three per cent of patients diagnosed with PDAC in the UK surviving for longer than five years. One of the reasons for this gruelling statistic is that PDACs are often diagnosed late, when the cancer cells have already spread to and wreaked havoc in other internal organs. Previously, several labs, including ours, noticed that some PDAC cells are more aggressive than others, more capable of re-growing new tumours from scratch. Now, we aim to understand what makes the more aggressive PDAC cells different from the rest of the cancer cells and how they contribute to the deadliness of this cancer. With that knowledge in hand, the broader aim will be to find anti-cancer drugs to target and kill the most dangerous cells that lie at the heart of PDAC.

A previous PhD student in our lab discovered that the more aggressive PDAC cells make and display large amounts of a certain protein – let’s call it protein X – on their cell surfaces. We say that the more aggressive cells are “marked” by protein X. This realisation was my gateway into finding out exactly how these two cell types, the more and less aggressive cells, differ.

First, I wanted to know whether protein X not only marks the more aggressive cells but whether it is directly responsible for making those cells more dangerous. Therefore I experimentally reduced or elevated the levels of protein X in PDAC cells we grow in the lab. Then I assessed whether the PDAC cells grew more or fewer, larger or smaller “organoids”, miniature replicas of pancreatic tumours. Astonishingly, the cancer cells actually grew less well when I removed most of protein X, or they divided and proliferated much more when they had more of protein X. This is a good indication that, in future, drugs might be delivered directly to protein X to eliminate the aggressive cells or convert them into tamer cells.

In the meantime, I am on the lookout for other characteristics that might distinguish between the more and less aggressive cells. From one of my experiments I have data hinting that the two cell types might in fact have different physical properties. However, until I’ve repeated these experiments I can’t be certain that this difference in appearance contributes to the more aggressive cells’ behaviour. But it is thinkable, for example, that the more aggressive cells can attach to other cells or blood vessels more easily, aiding their movement to the lungs or liver. These secondary tumours, also known as metastases, are the tumours that PDAC patients usually die from. Next, I need to determine whether there is a direct connection between protein X and the variations among the physical properties of the PDAC cells.

We really want to pin down the differences between the more and less aggressive cells so that hopefully researchers and pharmaceutical companies will be able to design and develop more effective drugs to tackle PDAC. In a few years, once we know more precisely what protein X is doing in the more aggressive cells, our findings might matter a great deal to patients. For the moment I am simply trying to find out more about how PDAC cells work and I know that can sound theoretical. However, I am certain that knowing why and how some cancer cells, clearly, are more equal than others will help patients in the future.


New Scientist Live

This weekend the ExCeL centre in London hosted an event called New Scientist Live, which was aimed at the general public and invited speakers across various fields, including Brain & Body, Technology, Earth and Cosmos. Additionally, there were stands and interactive stations run by various scientific institutions from across the UK and Europe, including The Francis Crick Institute, the Royal Society of Biology and the European Space Agency, to name a few.

But, to be honest, I was already sold when I saw the giant bacterium (precise species is still a matter of debate; could be E. coli) hanging from the ceiling:


Apart from this excellent demonstration of how cool cells are I want to write about two highlights.

  1. The talk by Molly Crockett on “What makes us moral?”
    Molly Crockett has a lab at the Department of Experimental Psychology, University of Oxford (but will be moving to Yale next year) where she and her research group study the neuroscience of “morality”. Dr Crockett’s talk was all-round excellent: from the clarity of her speaking, to the information on the slides, the science simplified enough to be understandable, yet retaining the references on the slides so that one can look up the original research (Crockett et al., 2014 and 2015, both open access!). The main finding of the 2014 paper was that people tend to be “hyperaltruistic”: when deciding whether to inflict painful electric shocks to oneself or another anonymous human being, the person deciding needed to be offered/paid more money to hurt another person. People also decided more slowly when the effects were to be felt by the other person rather than oneself. Importantly, and Dr Crockett emphasised this in her talk, these studies were conducted with real people and real electric shocks so that the results from their experiments might give us information about real life situations, as opposed to hypothetical ethical dilemmas. Possibly one of the most famous of these dilemmas is one in which a person needs to decide whether to save five people by actively sacrificing one, or to passively let five people die:moral-dilemmaIn the 2015 paper the authors then go on to test whether various drugs  – the antidepressant Citalopram, a selective serotonin re-uptake inhibitor and Levodopa, a dopamine precursor – can alter this moral decision making. Interestingly, the antidepressant reduced the overall number of electric shocks the deciders were giving out, both to themselves and to others. The hyperaltruism was preserved since deciders still gave fewer shocks to the receivers for the same amount of money. Levodopa, on the other hand abolished this hyperaltruistic effect:


    Bar charts showing the effects of citalopram and levodopa on harm aversion – copied directly from Crockett et al., 2015

    Obviously the talk and the papers go into much more detail, especially with the statistics used to evaluate these admittedly small effects. Lastly, it’s important to note that, as Dr Crockett pointed out, none of this means that researchers are working on, or should be working on, developing a “morality drug”…

  2. The science magazine Nautilus published by the MIT Press.
    Nautilus starts where the New Scientist stops, namely, where things get really interesting. To me, the New Scientist poses similar questions to the ones I might ask, but often fails to really answer them or provide a satisfactory explanation as to why there is no answer (yet). When I do read its articles they often leave me with more questions than before, which, of course, isn’t a bad thing. However, after reading a few articles of Nautilus it seems that this magazine is more thought-provoking: the articles are longer and maybe more on the creative side, but retain the references at the end, and the style of writing is more enjoyable to me. For instance, an article called “The Wisdom of the Aging Brain” by Anil Ananthaswamy discusses the possibility that there are neural circuits, or certain regions of the brain, that, with training and age, allow us to become wiser.
    So if any of my few readers is feeling particularly generous today then why not consider getting me the Sep/Oct edition…?


Crockett MJ, Kurth-Nelson Z, Siegel JZ, Dayan P, Dolan RJ (2014) Harm to others outweighs harm to self in moral decision making. Proceedings of the National Academy of Sciences 111: 17320-17325

Crockett Molly J, Siegel Jenifer Z, Kurth-Nelson Z, Ousdal Olga T, Story G, Frieband C, Grosse-Rueskamp Johanna M, Dayan P, Dolan Raymond J (2015) Dissociable Effects of Serotonin and Dopamine on the Valuation of Harm in Moral Decision Making. Current Biology 25: 1852-1859

CRISPR Digest #12

I know what you’re all thinking. When is she finally going to post about CRISPR again? It’s been too long. Well, you’re absolutely right and I’m going to make up for it. Last week I glimpsed a short article on the Science News site discussing the first CRISPR-modified cabbage. The botanist Stefan Jansson at Umeå University in Sweden “cultivated, grew, and ate a plant that had its genome edited with CRISPR-Cas9”. This is obviously very fitting since one of the pioneers of the technology, Emmanuelle Charpentier, carried out some of the seminal work at the same university between 2009 and 2014.

To cheer you up at the end of the summer, here have a listen to a short radio report on the CRISPR cabbage served with garlic and pasta – it’s in Swedish but that makes it all the more charming.

On a slightly more serious note though, I wrote about CRISPR gene-editing in the context of HIV infection in a previous post, and want to follow up here. In the last paper I discussed (Kaminski et al, 2016), the authors showed, as a proof-of-principle, that it is possible to use the Cas9 protein to cut out the HIV genome from infected T cells’ genomes, at least in a model of HIV infection. However, following this promising result two papers published more recently (both Wang et al, 2016 – sadly not me) show that the same process actually generates HIV mutants that can become infectious again. In particular, when the Cas9 protein cuts the HIV DNA that is integrated in the human genome, the human cells try to repair the cut in a process called non-homologous end joining (NHEJ). This correction mechanism, however, is prone to making errors and can sometimes lead to the creation of HIV DNA sequences that can replicate again. These HIV DNA sequences could then potentially produce new virus particles that can replicate, start a new round of infection and are, of course, resistant to the original CRISPR/Cas9 targeting, since they now contain new mutations. Once again science proves to be more fickle than originally thought; it really shouldn’t surprise us anymore.


Schematic showing how HIV can escape CRISPR/Cas9 editing – copied directly from Wang et al, 2016, Cell Reports

To return to and end on a more culinary note: not only has the world now seen CRISPR cabbage, but a report (Ren et al, 2016) published a couple of weeks ago demonstrated that the gene-editing technology also works in grapes, Chardonnay to be precise. The scientists modified the gene coding for the L-idonate dehydrogenase protein, which is involved in producing tartaric acid. So it is in theory possible to generate sweeter, or at least less acidic, grapes:


Genome-edited Chardonnay plant – copied directly from Ren et al, 2016


Kaminski R, Chen Y, Fischer T, Tedaldi E, Napoli A, Zhang Y, Karn J, Hu W, Khalili K (2016) Elimination of HIV-1 Genomes from Human T-lymphoid Cells by CRISPR/Cas9 Gene Editing. Scientific Reports 6: 22555

Ren C, Liu X, Zhang Z, Wang Y, Duan W, Li S, Liang Z (2016) CRISPR/Cas9-mediated efficient targeted mutagenesis in Chardonnay (Vitis vinifera L.). Scientific Reports 6: 32289

Wang Z, Pan Q, Gendron P, Zhu W, Guo F, Cen S, Wainberg Mark A, Liang C (2016) CRISPR/Cas9-Derived Mutations Both Inhibit HIV-1 Replication and Accelerate Viral Escape. Cell Reports 15: 481-9

Wang G, Zhao N, Berkhout B, Das AT (2016) CRISPR-Cas9 Can Inhibit HIV-1 Replication but NHEJ Repair Facilitates Virus Escape. Mol Ther 24: 522-526

Combining Art and Science

This is a confession. I love cells. However, if this were an essay for my German teacher at secondary school she would, given the name of this blog, award me a “Themenverfehlung” (basically completely missing the point of the essay question), which she did on a semi-regular basis. I could argue that in the broadest sense this post is also about cells, because cells were necessary for the creation of this work of art as well as for the analysis. But I admit that’s a bit of a stretch.

Anyway. I found this new paper published in Scientific Reports (Thurrowgood et al, 2016), which is simply entitled, ‘A Hidden Portrait by Edgar Degas’. The Australian research group, comprised of art curators and X-ray technology specialists, used a technique called X-ray fluorescence to study “Portrait of a Woman”, which hangs in the National Gallery of Victoria, Australia. Normal X-ray analysis had already revealed that an earlier portrait of a different woman lies underneath what is currently visible:

figure 1

Visible image of “Portrait of a Woman” (left) and conventional X-ray imaging (right) – copied from Figure 1

Conventional X-ray technology relies on the different densities of the materials/pigments in the painting. The denser areas absorb more of the X-rays and the X-ray film behind is less exposed than behind less dense areas, just like in a chest X-ray, for example. However, X-ray fluorescence is a more sensitive technique because it can detect specific elements in the painting. When atoms are hit by high energy X-rays some of the electrons close to the atomic nucleus (the “inner shells”) can be flung out of the atom entirely. This leaves a hole for electrons to fill and when these electrons “fall” into the inner shells energy is released in the form of electromagnetic waves, which are characteristic for different atoms:


Schematic of X-ray fluorescence – copied from this link

This technique is not entirely new, but as far as I understand this was the first time it has been used for a large-scale analysis of a painting. Using the physical properties of different atoms, Thurrowgood et al. created so-called elemental maps to determine which parts of the hidden portrait contained which elements.

figure 3

Elemental maps – copied from Figure 3

By analysing which elements are found in the same areas the researchers could trace back which pigments were used and therefore make educated guesses about the original colour of the painting. For example, the hair contained a lot of iron and manganese, which are often found together in the brown umber pigment.

figure 6

False colour image reconstruction of the hidden portrait of Mlle. Dobigny – copied from Figure 6

Mademoiselle Dobigny was one of Degas’ favourite models, but who knows why he kept her portrait for so long before deciding to paint over it. The reasons are certainly less obvious than in Georges Seurat’s painting “Young Woman Powdering Herself” (Courtauld Institute of Art, London): he concealed the only known self-portrait of his behind a mirror, watching the young woman who also happened to be his lover…

Reference and further reading:

Thurrowgood D, Paterson D, de Jonge MD, Kirkham R, Thurrowgood S, Howard DL (2016) A Hidden Portrait by Edgar Degas. Scientific Reports 6: 29594

New York Times article on Degas’ painting

Courtauld Institute of Art blog on Seurat’s painting

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.


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.


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.