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.

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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

A bit more pancreas

Last time there was an introduction to the overall anatomy of the pancreas, its basic functions and some of its diseases. Today we will go into a bit more depth but still keep it relatively simple.

Firstly, what does it look like inside a pancreas when one zooms in a bit more? In the following diagram the exocrine cells are shown in red – these are divided into:

  • Acinar cells. They are found in clusters that sometimes resemble bunches of grapes. In the diagram the blue spots represent the nuclei (where DNA is kept). However, these are actually found on the side of the acinar cells that does not face into the duct (i.e. the basal side; the apical side faces into the duct/lumen).
  • Ductal cells. These line the ducts through which the digestive enzymes – produced by the acinar cells – pass.
  • Centroacinar cells. A small group of cells that reside at the boundary of an acinus and a duct.
Diagram of exocrine and endocrine parts of the pancreas - copied directly from Wikipedia here

Diagram of exocrine and endocrine parts of the pancreas – copied directly from Wikipedia here

The endocrine portion of the pancreas, on the other hand, is shown in turquoise. These cells are organised into islets and secrete the hormones they produce directly into the bloodstream. They consist of:

  • Alpha cells. Produce the hormone glucagon, which opposes insulin and raises blood glucose levels.
  • Beta cells. Produce the hormone insulin, which decreases blood glucose levels by stimulating the uptake of glucose into muscle and fat cells.
  • Delta cells. Produce the hormone somatostatin, which opposes a lot of other hormones in the body and, in particular, can slow down digestion.
  • Gamma cells. Produce so-called pancreatic polypeptide, which regulates secretion of other hormones in the pancreas.
  • Epsilon cells. Produce the hormone ghrelin, which is also known as the “hunger hormone” and signals to the brain that the stomach is empty.

Overall the two parts of the pancreas perform complementary roles: the exocrine pancreas helps to physically digest food coming from the stomach, whereas the endocrine pancreas makes sure that the glucose released into the blood due to the digestive processes is used/stored properly.

Secondly, people who are not scientists sometimes ask me how we actually study both normal and disease processes in the lab. Focussing on pancreatic ductal adenocarcinoma (PDAC), here is a brief overview of the systems used in the lab to gain a better understanding of what is going on in human disease.

  1. The easiest system to use are so-called (pancreatic cancer) cell lines – these are cells that were once taken from a patient and then cultured in the lab (in vitro). So although they are originally from a very relevant biological setting, the continuous culturing in the lab means that they are no longer physiological. For example, they grow in flat sheets on plastic trays, do not interact with any other cells and often have mutations that go above and beyond what is found in a real cancer. However, they allow relatively quick, controlled experiments to be conducted and are therefore still indispensable.
  2. More recently there has been a surge in research involving (pancreatic) organoids. These are mini-organs that are functionally closer to the real organ being studied and also have three dimensional structures that are more physiological. However, they need to be kept in relatively specialised conditions and are a little bit more tricky to manipulate than the cell lines.
  3. Since it is impossible (for a lot of reasons, including ethical ones) to conduct experiments on humans, cancer biologists most often turn to mice since they are also mammals and are genetically similar to us – we share approximately 90% of our DNA sequences. Mouse models of cancer allow complicated, intricate and biologically relevant experiments to be carried out, but they do take more time and need to be planned very carefully. Guerra & Barbacid (2013) have written a review specifically on PDAC mouse models.
  4. Data from human cancer biopsies. Increasingly, as sequencing whole genomes is becoming cheaper and easier to do, labs use DNA sequencing data from patients to compare some of their results from the mouse experiments. Biopsies can also be used to look at the histology (micro-anatomy) of certain stages or types of cancer in humans.

In the end, these techniques are used together, since all of them have strengths and weaknesses, allowing (hopefully) the most accurate description of what is going on in a certain (disease) scenario.

Lastly, what exactly do we use all these methods and systems for; what are the outstanding questions surrounding PDAC? Well, there are quite a few, but here are some of the more common ones: Why do most PDACs arise in the head and not the tail of the pancreas? Why are they so prone to metastasise (spread through the body)? How can we detect PDAC sooner and, importantly, distinguish it from inflammation of the pancreas? Where exactly (which cells) do PDACs come from? What roles do stem cells play in all of this? (If you have the answers to any of these questions, please do not hesitate to get in touch.)

Reference:

Guerra C, Barbacid M (2013) Genetically engineered mouse models of pancreatic adenocarcinoma. Mol Oncol 7: 232-247