Inducing PhD Students

What a feat of architecture and design: the new Francis Crick Institute on Brill Place right next to (West of) St. Pancras Station in London. Apparently the ground floor was built first and then extended up and down simultaneously; I didn’t know that was possible. If you decide to watch the video, I recommend turning off the sound and ignoring the spectres and shadows of people.

Now, sadly, I don’t have a picture of us new PhD students posing outside or inside the building because it isn’t finished yet. As far as I am aware, there have been issues with the air conditioning and parts of the basement vibrate too much for sensitive instruments, such as microscopes, to be set up. The latter is perhaps not surprising considering that the Crick is wedged right between St. Pancras and Euston stations…

Last week we were induced/introduced/inducted to the life of being PhD students. The CEO of the Crick, Paul Nurse, who happens to have won a Nobel Prize, talked to us about how we shouldn’t work too much, try to step out of our projects from time to time to gain an overview, and remember that it is a privilege and not an entitlement to be doing a PhD at the Crick. He also said that leaving academia after this four-year PhD should not be regarded as a failure and that we would receive support in doing other things. I’m a bit sceptical because he also heavily implied that we were not to disappoint the institute, but we’ll see.

As part of the degree we will also have to complete ten days of training per year, which should cover all our bases (according to the Researcher Development Framework; gone are the days of the solitary, uncommunicative, mad scientist):

RDF

In between the serious talks there were plenty of opportunities to get to know – or schmooze with, as one of the students put it – the other students over coffee/tea/beer/wine/pizza/sandwiches. During the first icebreaker session we introduced ourselves and had to provide a memorable fact: they ranged from having started a cupcake business, to being fond of planes, teaching children the piano, appearing in a television series as a child and even being Austrian (!).

We also had a lecture on scientific integrity and ethics (in research). The take-home message was, as always, to be honest. We were shown how not to manipulate or massage data. Luckily, we will be given training in Photoshop and Illustrator so that we can handle our images correctly.

Two half-days were spent listening to the leaders of the so-called Science & Technology Platforms (STPs). These are specialised labs that usually do not have their own projects, but rather lend their equipment and expertise to the other research groups in the institute to enable them to perform experiments they would not be able to do on their own. The STPs include, among others, advanced microscopy facilities (both light and electron microscopy), flow cytometry (to analyse cells at the single-cell level and even sort them), bioinformatics and statistics, DNA/RNA sequencing and peptide chemistry/synthesis. However, the one I was most surprised by was the “scientific instrument prototyping” group – they basically create new scientific machines that no company has made before. They probably conform to the crazy inventor stereotype the most. Overall, the services offered by the STPs seem absolutely incredible and hopefully many of us will actually get to work with them.

After a week of what I thought would be a relaxed introduction to the next four years I am asking myself the question how I used to be able to sit through and concentrate during lectures?! It’s really not that long ago. And also, how have I never really reflected upon the fact that most speakers/lecturers are white middle-aged men? With the exception of the administration team, the communications/engagement team, the scientists in charge of the animal facilities and the professor who gave the talk on ethics, all of the speakers were men. Bear in mind that in our year women make up almost 70% of all students.

The last activity was organised by current PhD students and called “What Mad Pursuits“, after a book by Francis Crick. A few students from each year outlined their take on scientific discovery, told us a bit about their research, gave us refreshing examples of how and how often they’ve made mistakes (e.g. putting the microscope slide the wrong way up for two weeks before figuring out why there was no image; setting gloves on fire etc.) and gave us some advice. One student recommended reading this paper (Schwartz, 2008) – The importance of stupidity in scientific research:

Productive stupidity means being ignorant by choice. Focusing on important questions puts us in the awkward position of being ignorant. One of the beautiful things about science is that it allows us to bumble along, getting it wrong time after time, and feel perfectly fine as long as we learn something each time. No doubt, this can be difficult for students who are accustomed to getting the answers right. […] The more comfortable we become with being stupid, the deeper we will wade into the unknown and the more likely we are to make big discoveries.

References:

Medawar PB (1979) Advice to a Young Scientist. Basic Books, New York.

Schwartz MA (2008) The importance of stupidity in scientific research. Journal of Cell Science 121: 1771

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

An Introduction to the Pancreas and its Cancer(s)

Given that the four-year PhD I am about to embark on is being partly funded by Cancer Research UK (CRUK), why not start with a short video they have put together containing ten things about that pancreatic cancer that you may (not) have known:

Firstly, is there anything more to its anatomy than “being a small organ in the abdomen”? Why yes, funny you should ask. The pancreas reaches up to 15 cm in length in humans and is a J-shaped structure, apparently a bit like a hockey stick. The organ is not symmetric, rather it is made of a head (left), body (middle) and tail (right), as shown below. In the head the main pancreatic duct merges with the common bile duct before they join into the duodenum, where food is further digested after it leaves the stomach.

Screen Shot 2015-09-04 at 22.08.59

Cartoon illustration of a human pancreas – copied directly from Hezel et al, 2006

As is often the case in biology – and this applies from the level of individual proteins to a whole organism – there is an intricate relationship between structure and function. The pancreas has two main functions: firstly, it contains endocrine cells that produce hormones, such as insulin, to regulate glucose balance (or homeostasis). Secondly, it contains exocrine cells, which make up the majority of the organ, that produce enzymes to aid food digestion. These two categories of cells therefore work together and coordinate the body’s metabolic response to food consumption.

Not all animals have pancreases as complex as those found in mammals since they have evolved over time. Worms, for instance, have some specialised gut cells that produce a substance similar to insulin. Ancient sharks and some fish contain organs in which the exo- and endocrine cells are found together. Fruit flies astonishingly produce insulin in their brains and, in particular, those cells develop from a completely different tissue in the embryo – called the ectoderm – than in other animals, where the pancreas stems from the endoderm. In amphibians and mammals the anatomy becomes more complex with characteristic “islets” of endocrine cells. (See Stanger & Hebrok, 2013 for more details.)

Since I am the daughter of two doctors I am usually interested in the pathological side of human biology. What sort of diseases befall the pancreas? Possibly the first that comes to mind is (type I, auto-immune type) diabetes in which the pancreas fails to make enough insulin because the body is attacking its own beta cells that normally produce insulin. Other than that the pancreas can of course become inflamed like any other organ and this is known as pancreatitis. It is caused, among other things, by high doses of alcohol. Lastly, the pancreas can become cancerous.

Although there are a few different types of pancreatic cancer the focus will lie on pancreatic ductal adenocarcinoma (PDAC) since it is both the most frequent and also the best understood type. It is one of the deadliest types of cancer because it often goes unnoticed until the tumour has disseminated (or metastasised) in the body – fewer than 10% of people who are diagnosed survive for longer than five years.

Therefore it is important to find out more about PDAC. But for the moment there is a lot we do know, decades of hard work that are often frustratingly glossed over. For instance, the genetic mutations that start and maintain PDACs are well known. Among them are activating mutations in a famous oncogene – a gene whose overactivation contributes to cell proliferation and cancer – called KRAS, and deletions of tumour suppressors – those genes/proteins that act as checks and balances and stop cells from overproliferating – such as p16 and p53. Moreover, it is well known when these mutations occur during the development of the cancer. The following image shows how some PDACs form: from healthy tissue to slightly abnormal tissue until it invades into the rest of the body.

Screen Shot 2015-09-04 at 22.42.00

Histology of normal (left), dysplastic (middle) and malignant (right) pancreatic tissue – copied directly from Bardeesy & DePinho, 2002

As for treatment, the most effective method, if successful, is surgery. However, this often involves removing the head of the pancreas as well as parts of the duodenum and this, in turn, means that the stomach has to be surgically joined directly to subsequent parts of the digestive tract, making it a complex procedure. In addition, patients receive radio- and/or chemotherapy, which “targets” most proliferating cells. Targeted therapies that are specific to the cancer cells, as opposed to healthily dividing cells, are, as far as I am aware, not particularly established yet for pancreatic cancer.

For surgery to be effective the cancer needs to be detected at earlier stages. In other words, better diagnosis procedures need to be developed. Recently, two papers attracted some attention because they uncovered methods that could potentially make diagnoses easier using either blood (Melo et al, 2015) or urine (Radon et al, 2015) samples. However, as CRUK rightly point out, these techniques need to be refined for them to be able to tell true cancers from chronic pancreas infections.

And on that cheery note… Next time you can look forward to learning a bit more about how PDAC is studied in the lab and pancreatic anatomy in slightly more detail.

References:

Bardeesy N, DePinho RA (2002) Pancreatic cancer biology and genetics. Nat Rev Cancer 2: 897-909

Hezel AF, Kimmelman AC, Stanger BZ, Bardeesy N, DePinho RA (2006) Genetics and biology of pancreatic ductal adenocarcinoma. Genes & Development 20: 1218-1249

Melo SA, Luecke LB, Kahlert C, Fernandez AF, Gammon ST, Kaye J, LeBleu VS, Mittendorf EA, Weitz J, Rahbari N, Reissfelder C, Pilarsky C, Fraga MF, Piwnica-Worms D, Kalluri R (2015) Glypican-1 identifies cancer exosomes and detects early pancreatic cancer. Nature 523: 177-182

Radon TP, Massat NJ, Jones R, Alrawashdeh W, Dumartin L, Ennis D, Duffy SW, Kocher HM, Pereira SP, Guarner  L, Murta-Nascimento C, Real FX, Malats N, Neoptolemos J, Costello E, Greenhalf W, Lemoine NR, Crnogorac-Jurcevic T (2015) Identification of a Three-Biomarker Panel in Urine for Early Detection of Pancreatic Adenocarcinoma. Clinical Cancer Research 21: 3512-3521

Stanger BZ, Hebrok M (2013) Control of Cell Identity in Pancreas Development and Regeneration. Gastroenterology 144: 1170-1179