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.

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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:

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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

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:

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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:

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    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…?

References:

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

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…

First PhD Checkpoint

In December, we – the (mostly) young and innocent first-year PhD students at the Francis Crick Institute – gave our first formal talks. Each student had to present the outline of their project to all the other students in a ten minute slot. This was probably intended mostly for our own benefit to ensure that we had at least a rough idea of what we will be working on for the foreseeable future. Here I’d just like to mention a few of the talks that I found particularly interesting, but it’s worth saying that I thought the overall level of presentations was very high and the questions we ended up asking each other were well thought through. Overall a very enjoyable experience.

  1. To begin with there were a couple of talks from students in the same lab studying the interactions of cancerous cells with the immune system. In particular, they are trying to find out how dendritic cells – cells that normally alert effector cells of the immune system that something is wrong (e.g. an infection is happening) – can sense the presence of dead/dying tumour cells and relay this information to so-called T cells. The two students are looking at both the molecular mechanism by which this happens, but also whether precursors of dendritic cells in the bone marrow have similar abilities.

  2. A few students in the programme are working on mathematical/computational projects and will never have to wear a lab coat. For example, one lab is interested in understanding how non-cancerous cells near a tumour interact with the cancer cells and influence their ability to move. To do this one can mathematically model the movement patterns of the “cancer-associated fibroblasts” and how they interact with extracellular proteins to form tracks for the cancer cells to move along. In the simplest terms (and that’s the only level at which I understand this), the model relies on the Morse potential, which is normally used to understand how atoms interact but can be scaled up to model interacting cells. Here is a video of a fibroblast interacting with a breast cancer cell; the accompanying text is maybe overly simplistic, but you get the gist:

    Another student is studying how sheets of cells move together, both during embryonic development and tumour formation. This relies (roughly) on modelling cells as polygonal shapes that stick together via their vertices. Yet another “dry” project is investigating how cancers evolve over their lifetime: this is done by collecting DNA sequencing data from cancer cells at various stages of their development and inferring which changes happened when.

  3. Since it is generally the metastases that are the deadly part of cancers it is important to  understand how cells move. There is, of course, a lot of information about this already but here the aim is to find out more about how different cancer cells (e.g. breast cancer and skin cancer) share certain features in their movement patterns.

  4. Not all labs in the institute study cancer. Some labs focus on basic research using yeast as a model organism. Both yeast cells and our cells contain a lot of DNA that is not translated into protein; for a long time all this DNA was termed “junk” and nobody bothered with it too much. It is becoming increasingly clear that this so-called non-coding DNA can still play various roles in the cell and some of these may be deleterious. Therefore one student is studying how cells prevent the activation (transcription) of some of these stretches of DNA.

  5. Another major branch of the institute deals with infectious diseases and the immune system more broadly. Two talks that I enjoyed on this front were given by students again working in the same lab. They are studying “neutrophil extracellular traps” (NETs), which I had never heard of before and sound quite cool. Neutrophils are a cell type of the immune system and are the first to react to infectious agents. By releasing very broad-acting antimicrobials they try to quell an infection in its infancy, but by doing so they also cause the four main symptoms of inflammation: pain, heat, redness and swelling. NETs are made of DNA and proteins from the neutrophils and are sticky. One of the students is looking into how NETs can exacerbate atherosclerosis, while the other is finding out how NETs physically trap invaders, such as the fungus Candida albicans.

  6. Lastly, and because it would pain me not to mention CRISPR, one student is trying to find a way to control the sex ratio of offspring in laboratory animals, specifically mice. While at first glance this might seem dangerous or cruel, it is actually part of an effort to reduce, replace and refine the use of animals in research. For example, if you are studying prostate cancer or ovarian cancer half of the experimental animals born are completely useless and end up being “wasted”. At the moment, some agriculture relies on physically sorting sperm cells into those carrying X or Y chromosomes and using mainly those with X chromosomes for in vitro fertilisation (because far fewer male animals are needed). Although this is a very accurate method it is expensive and time-consuming. Since CRISPR is precise and can be genetically encoded it would virtually work by itself once established.

This is by no means an exhaustive list of the topics covered by our projects, but hopefully it’s an interesting glimpse into what we are currently spending (almost all?) of our brains and energy trying to figure out.

These talks will be complemented with a so-called thesis committee meeting later this month: here each student will present a very similar talk to three professors or group leaders, who will be advising the project from an outside perspective. Hopefully being locked in with three clever and knowledgeable people will conjure up constructive criticism as well as (even more) new ideas!

Seminars with Sirs

In addition to normal lectures and lab/project work, the M.Sci. biochemistry course here at Cambridge also includes weekly seminars, which focus either on a set of landmark papers or on a particular methodology. The general idea of these seminars is probably “to encourage students to think, to learn, and to think about learning, so that they ultimately develop the skill—and courage—to train themselves” (Raman (2015)). Raman argues in the eLife article that understanding past research in its historical context, whose results and implications are now taken for granted, is a key step to being able to come up with interesting questions and the appropriate experimental approaches to tackle these. Maybe in a few years we’ll know whether reading and discussing these landmark papers actually had this desired effect.

Two weeks ago the seminar was entitled “Greatwall and the control of mitosis” and was held by this charming fellow:

hunt

He is none other than (Professor Sir) Tim Hunt, who won a Nobel prize for Physiology/Medicine in 2001 together with Paul Nurse and Lee Hartwell for their “discoveries of key regulators of the cell cycle”. I would wager that the foundation experiments leading to this prize are taught in all biology undergraduate courses and so the seminar was not actually about these, but rather on the follow-up experiments conducted by Tim Hunt and his lab. In particular, the seminar was about the intricacies of cell cycle regulation by proteins called phosphatases. Phosphatases are enzymes that remove phosphate groups from other proteins and thus catalyse the opposite reaction of protein kinases, which add phosphates to proteins, usually at the amino acids serine, threonine or tyrosine. Some of what we discussed was summarised by Mochida & Hunt (2012), but the exciting and interesting parts of the seminar actually consisted of listening to Tim Hunt explain which experiments he agreed with and why, and perhaps more entertainingly, which experiments he does not believe and why.

Then a week later the seminar was hosted by John Walker:

walker_postcard

(Professor Sir) John Walker – surprise, surprise – also won a Nobel prize (Chemistry, 1997), together with Paul Boyer for “their elucidation of the enzymatic mechanism underlying the synthesis of adenosine triphosphate (ATP)”. [Incidentally, John Walker seems quite proud of being a knight of the British Empire: I caught a glimpse of the inside of the case for his glasses, “Sir John Walker + telephone number”.]

In this seminar we also briefly recapped the basics of ATP production by mitochondria, but again this is something we covered in first and second year. However, we then discussed the landmark paper (Abrahams et al. (1994)) describing the structural features of the enzyme ATP synthase that catalyses the production of ATP from ADP and phosphate. Incidentally, that paper was dedicated to Max Perutz for his 80th birthday, since he was involved in discussing this research at the MRC Laboratory of Molecular Biology. Subsequently, we moved on to more current topics relating to ATP synthase, such as its possible involvement in the formation of the mitochondrial permeability transition pore (Giorgio et al. (2013)).

Interestingly, although Hunt and Walker are of course entirely different people, there were two striking similarities between them: firstly, both of them are still active researchers who clearly are still excited by science and their experiments. Secondly, both are embracing new techniques and technologies, which were not available when they started out as scientists. For example, Walker and his group use molecular dynamics simulations (quantum mechanics and computation) as well as cryo-electron microscopy to study ATP synthase. Hunt also uses computational modelling to gain more insights into the complex networks regulating progression through the cell cycle, and Paul Nurse, who used to be a “simple” geneticist, has now essentially become a systems biologist. Hard work, joy at doing science and being receptive to new technologies all seem to be hallmarks of good researchers – best to bear this in mind.

References:

Abrahams JP, Leslie AGW, Lutter R, Walker JE (1994) Structure at 2.8-angstrom resolution of F1-ATPase from bovine heart mitochondria. Nature 370: 621-628

Giorgio V, von Stockum S, Antoniel M, Fabbro A, Fogolari F, Forte M, Glick GD, Petronilli V, Zoratti M, Szabo I, Lippe G, Bernardi P (2013) Dimers of mitochondrial ATP synthase form the permeability transition pore. Proceedings of the National Academy of Sciences of the United States of America 110: 5887-5892

Mochida S, Hunt T (2012) Protein phosphatases and their regulation in the control of mitosis. Embo Reports 13: 197-203

Raman IM (2015) Teaching for the future, Vol. 4.; eLife 2015;4:e05846