Exactly a century ago, D’Arcy Thompson published his book On Growth and Form.
I’ve spoken about Mr. D’Arcy before, but as it is the 100-year anniversary of his masterwork, I feel it fitting to revisit the topic. Since mentioning him last, I have finished reading his book, and have also started to write up my thesis. I bring up my thesis because my work is related to D’Arcy’s work in the sense that I have been trying to bridge the gap between biology and physics, and I predict that some of my reading will inspire me to write more (hopefully more of my thesis but presumably also more on the general topic of bio-meets-phys).
Mr. D’Arcy wrote On Growth and Form to collect his observations on the mathematical principles of nature. He explains how biological phenomena of form and growth closely resemble physical and mathematical principles. Especially for some of the more simple examples (e.g. the shape and size of single or doublets of cells) the similarities between biology and physics (e.g. single and doublets of bubbles) are almost uncanny. These simple systems can easily be described using simple formulas, and he suggests that even more complex systems can be explained in a similar way (though he remarks that it will take a lot of formulas and paper space, luckily we have computers now). In 1917, this idea was pioneering, to say the least. Bio-mathematics and biophysics were nowhere near being the hot topics they are today.
One of the events organised for the anniversary of On Growth and Form, was the exhibition A Sketch of the Universe at the City Art Gallery in Edinburgh, showcasing works of art that were inspired by the book, or by the idea that mathematics and biology are closely intertwined. The exhibition is closed now, but this weekend I did get the chance to go visit it.
So, I present to you, some of the highlights that I found interesting or cool-looking:
“I know that in the study of material things number, order and position are threefold clue to the exact knowledge; and that these three, in the mathematician’s hands, hurnish the first outlines for a sketch of the Universe.” (D’Arcy Thompson, On Growth and Form)
“For the harmony of the world is made manifest in Form and Number, and the heart and the soul and all the poetry of Natural Philosophy are emodied in the concept of mathematical beauty.” (D’Arcy Thompson, On Growth and Form)
“The waves of the sea, the little ripples of the shore, the sweeping curve of the sandy bay between the headlands, the outline of the hills, the shape of the clouds, all these are so many riddles of form, so many problems of morphology.” (D’Arcy Thompson, On Growth and Form)
You can read more about D’Arcy Thompson, On Growth and Form and some of the events being organised this year in honour of the 100 year anniversary, here. And presumably in the near future on this very blog.
[Note: Again, I realise that D’Arcy Thompson’s last name is “Thompson” so “Mr. Thompson” would be a more appropriate title (or Prof. Thompson) but I just cannot resist his practically Austenesque first name.]
Two weeks ago, I told you that physics and cancer are, perhaps counterintuitively, intermingled and that this relationship has biological and clinical implications. I outlined how mechanical forces act on cells and tissue, and perhaps are responsible for one of the many ways of cancer progression.
In this post, I’d like to tell you about how being able to detect mechanical properties of tissue can help with diagnosing diseases. So while the previous post was more about how physics can influence the biology of a tissue, this time I’d like to focus on how biology can dictate physical properties of a tissue.
A very important issue to point out, before going into the differences between healthy tissue/cells and cancer, is the size scale we are considering. Depending on whether we are talking about cells (µm size range) or tissues (100s of µm to mm), we can make quite opposite conclusions: several studies have shown that tumour cells are softer than healthy cells (of the same tissue type), while tumour tissue is stiffer than healthy tissue.
First the cells. Experiments such as Atomic Force Microscopy (which I mention because I have used it myself) show that especially metastatic tumour cells are softer than healthy cells. If we consider what cells do during metastasis, this actually makes sense. (Metastasis is the process where cells migrate away from the initial tumour and spread to other parts of the body.) A softer cell is able to squeeze through other cells, and through the wall of a blood vessel, allowing it to travel to elsewhere in the body. This different mechanical property allows it to behave in its particular way. Knowing this property allows us to predict the aggressiveness (or invasiveness) of a certain cancer. If the tumour has cells that are much softer than other, it is usually a more aggressive type of cancer.
This difference in mechanical properties not only makes sense if we consider the behaviour of the cells, it can also help make prognoses and decide on what type of treatments to use.
Next, on a larger scale, tumours are stiffer than healthy tissue. This is exactly what we feel when we are “looking for lumps”. A bit of tissue feels different, namely stiffer, than what it should be. The reason tumours are stiffer is not actually due to the (softer) cells it contains, but due to what sits in between the cells: the extracellular matrix. The extracellular matrix is a very structured meshwork of structural proteins that acts as a scaffold for the cells: it provides the tissue with structural integrity, cell organisation and mechanical strength. For example, there are a lot of extracellular matrix proteins in our skin, which is why it is, well, our skin (hurray for circular reasoning): a sturdy barrier between the outside and the inside of our body. In healthy tissue, the extracellular matrix is usually very well organised. The fibers making up the matrix are regularly cross-linked and have and neatly organised. However, the matrix in tumourous tissue is chaotic. In essence, was “built” too quickly. In this fast-growing bit of tissue, the scaffolding had to be assembled fast to support the rapidly dividing cells. As a result, the fibres are not well organised and the crosslinking is random. It is as if the scaffolding of a building was built too quickly, so rather than nicely structured, there are random beams sticking out in all directions. As a result, pushing down on the matrix does not compress it as much, and it feels stiffer.
At a tissue level, these differences in mechanical properties are very useful for diagnosing cancer. Because of different mechanical properties, we can feel lumps, but we can also image it using techniques such as ultrasound, MRI and other imaging techniques. Due to different physical properties, the cancerous tissues interacts differently with whatever wave (light, sound, …) we are using to try and detect it. Thank you physics!
To wrap this up: the physics of cancer is important, and useful, and interesting, and cool and definitely worth researching. And this is why interdisciplinary research is not only a fancy buzzword, it can also increase our understanding certain phenomena and come up with better diagnoses and treatments by approaching the problem from a completely different perspective.
This subject was the topic of my second FameLab performance (Scottish regionals), which ended in a little song (to the tune of “What a Wonderful World” by Sam Cooke), in which I wanted to highlight the importance of interdisciplinary research and how studying diseases from a physics perspective can only be productive:
You know, cancer’s about biology
And perhaps a bit of chemistry
But I’m telling you there’s physics too
There’s physics happening inside you
With one subject you can never be sure
Put them together, and we might find a cure
And what a wonderful world that would be…
Some references I used to verify that my thoughts on this subject were not completely unsubstantiated:
Baker EL, Lu J, Yu D, Bonnecaze RT, Zaman MH. Cancer Cell Stiffness: Integrated Roles of Three-Dimensional Matrix Stiffness and Transforming Potential. Biophysical Journal. 2010;99(7):2048-2057. doi:10.1016/j.bpj.2010.07.051.
Suresh S. Biomechanics and biophysics of cancer cells. Acta biomaterialia. 2007;3(4):413-438. doi:10.1016/j.actbio.2007.04.002.
Kumar S, Weaver VM. Mechanics, malignancy, and metastasis: The force journey of a tumor cell. Cancer metastasis reviews. 2009;28(1-2):113-127. doi:10.1007/s10555-008-9173-4.
Plodinec M, Loparic M, Monnier CA, Oberman EC, Zanetti-Dallenback R, Oertle P, Hyotyla JT, Aebi U, Bentires-Alj M, Lim RYH, Schoenenberger C-A. The nanomechanical signature of breast cancer. Nature Nanotechnology. 2012; (7):7 57–765. doi:10.1038/nnano.2012.167
If you are confused by the title, that’s okay. Usually, when we read something about cancer, it is about something biology-related, for example about specific mutations or the environmental conditions that increase cancer risk. A lot of research is happening with regards to the biology and biochemistry of cancer: which tumour suppressor genes are mutated in certain cancers, what are the effects cancer has on someone’s health, what drugs can we use to treat a cancer, … ? But, perhaps surprisingly, studying the physics of cancer also has its merit. Why, it’s a whole field in itself!
So I’d like to talk a little bit about this topic, the physics of cancer, and in this first part, I will focus on how physical forces can change the behaviour of cells (and how this might be involved with disease).
Cells not only sense their biological environment, they also feel their physical environment. They sense the stiffness of the cells and protein structures around them, they sense how other cells are pushing and pulling on them, and then they react to it. And these mechanisms could actually be quite important for the development and progression of cancer.
Recent research showed that the cells surrounding a tumour are under mechanical stress because of the growth of the tumour. As a tumour grows, it pushes on its environment. So the – initially healthy – cells in its direct surroundings, feel a pressure. In this specific study, they showed that this pressure caused the cells to start a mechanical response pathway leading to the upregulation of a protein β-catenin. This protein is involved in activating certain pathways involved in cell proliferation.
Which is exactly what its upregulation leads to in cancer. In the case of colorectal cancer (which, if you remember, I am particularly interested in), a mutation of Apc (adenomatous polyposis coli, in case you were wondering) also leads to an accumulation of β-catenin amongst other things. The APC protein has been linked to many functions, but the best known is its involvement in forming a complex that binds to β-catenin and tagging it for destruction. That way the proteins involved in protein recycling know that the β-catenin proteins can be cut up. But when APC is mutated, β-catenin gets tagged and starts piling up and doing some of its jobs a little bit too well, including inducing proliferation pathways.
So back to the study, if healthy cells are experiencing a constant pressure (due to a big bad tumour growing into their space, or – as they tested in the study – artificially caused pressure), they start acting more “cancer-like”. This suggests that mechanical activation of a tumorigenic pathway, in this case, the β-catenin pathway, is a potential method for transforming cells.
This is just one example of how physics and cancer are potentially related. As a side note, I myself am also interested in how cells respond the mechanical stresses, which prompted me to do an experiment where I placed weights on top of cells.
This subject was the topic of my first FameLab performance, which ended in a little song (to the tune of “Friday I’m in Love” by the Cure). It’s sung from the perspective of a cell that is stuck next to a growing tumour:
Hello there, I am a cell.
Feeling healthy, fit and well.
Life is good, yes, life is swell.
But my neighbour’s got it worse.
Something about him does not belong.
The way he pushes is just wrong.
They say in him the force is strong,
they say he’s got the force.
He takes up so much space.
And is always getting up in my face.
It’s putting me in a stressful space.
You could say he’s left his mark.
It’s like swimming with a shark.
He’s pushing me towards the dark,
the dark side of the Force,
the dark side of the Force.
In the past month, I took part in a science communication competition called FameLab, first in the local heat and then in the Scottish final. It was a really fun and educational experience (and by educational, I mean that I learned something, even if it technically was also supposed to be educational for the audience). And even though I (unfortunately) did not make it through to the national final, it was a fabulous – or should I say famelabulous (hahahaha and I didn’t even come up with that) – thing to be part of.
Anyway, FameLab is a competition where STEMers (scientists, engineers, and mathematicians) get 3 minutes to talk about a scientific concept of their choice. Yes, only 3 minutes! And as if that wasn’t hard enough, during those 3 minutes, they get judged on content, clarity, and charisma. I mean obviously you have to talk about something worthwhile and don’t jumble things up too much, but having to be charismatic as well, that just sounds like too much of a challenge!
Without going too much into detail on what I talked about exactly – I might elaborate on that in some other post, though I’m sure you can find it with some smart googling, in any case it was about the physics of cancer, – I thought I might give my insights on how to give a 3-minute talk. And most things can be extrapolated to longer talks.
Well, it’s not like I won, so there is no reason to believe anything I tell you. Also, it’s all pretty obvious stuff that they teach you in any presentation skills course. You know: stick to the key points (the audience only remembers three things or so of what you say), don’t use too much jargon but don’t dumb it down either (be like Shakespeare, jokes for all, and the occasional clever twist for the snobs to smile about), be your own charming self (no need to act), breathe, don’t faint, imagine the audience with no clothes on,… all the obvious things.
I guess the best lesson I learned was that I have an inescapable future as a superhero. “Inevitable avenger” is an anagram of my name and that has to be the most awesome thing someone has ever used to introduce me.
I’ll be using this for everything now.
(Yes, the only reason for this post was to brag about my new cool nickname.)
For the most part, I was on holiday.
*cue 3-line rant about how amazing it was*
I can’t stress enough how amazing it was – obviously; New York is awesome – and how much delicious food we had – lobster sandwiches and NY pizza and (no-Turkey-for-me) Thanksgiving dinner – and how sad I am about being back in the real world.
But alongside the fun and leisure, I also volunteered for a science education event organised by RockEdu, Rockefeller University’s educational outreach office.
Apparently, it was surprising that I would give up half a day of my holiday to volunteer at an outreach event. But to me, it was an interesting experience, an opportunity to try out my outreaching enthusiasm in a different context, make some useful connections and most of all, a whole lot of fun! After this experience, I’d really like to pitch a new idea: EduTourism (#EduTourism, spread the word, folks): volunteering in educational programmes while on holiday. It gives a new perspective on outreach, it gives you a good excuse to visit another academic institution, and it is a perfect way to interact with locals! Also, it makes you feel that your trip was more than just a – albeit entertaining – waste of money.
What I especially liked about the RockEdu lab, was how organised everything is. Instead of the usual format of a science education team, i.e. a bunch of volunteering PhD students and PostDocs who want a break from their research and the occasional coordinating staff member, RockEdu has a team of 5 or 6 people permanently working in outreach. They write grants, create activities, set up mentoring programmes, coordinate summer projects, etcetera etcetera. Moreover, they have a lab space that is exclusively and specifically used for science education. Instead of activities carried out in some corner between labs or in an improvised table-based laboratory missing crucial equipment or sockets, these benches are meant for education! Classes can come in – for free – and participate in a science experiment tailored for their age and level.
So I spent part of the day helping a group of 16ish-year-old AP bio students through a GFP purification process, something I myself knew about but had never actually carried out. Using blue flashlights and yellow goggles, the whole process could be followed closely, which was pretty neat. We learned about proteins, fluorescence, jellyfish, what doing a Phd is all about. We ran a gel and looked at some GFP-expressing worms as an example of an in vivo application. I thought it all was pretty cool and the students also seemed to have enjoyed themselves (while learning something, of course).
Overall, I’m really glad I took the time to participate in EduTourism, and totally hope that this will become an actual thing.
Okay, I realise there is no easy answer to this.
But let’s assume that living forever wouldn’t turn you into a shriveled old raisin and that you wouldn’t have to watch your loved ones die and that this somehow would not lead to (even more) overpopulation.
Short story, let’s just imagine your answer to that question is: “Yes, totally!”
Unfortunately, immortality is a fictitious feat for comic book superheroes. That doesn’t keep us humans from trying to reach immortality in a certain sense, in the hope of leaving a lasting mark on the world.
Immortality, or prolonged aging, is of great interest for science. Living too long isn’t too great for our cells; we stop replacing old cells and start wearing out; and longer living is associated with age-related diseases with the most pertinent being cancer.
But there could be hope: not all animals develop cancer !
Let’s start underground. Naked mole rats (Heterocephalus glaber), for example, live long past their rodent cousins such as rats and mice; up to 17 years in the wild and even over 30 years in captivity. Additionally, they don’t develop cancer. Just for reference: mice barely make it to 4 years and often die of cancer.
Naked mole rats – let’s call them NMRs for brevity – are already quite odd creatures. Aside from being very strange looking (I don’t want to hurt their feelings too much), they are quite tough: they don’t feel the sting of acids or burn of chili. I, on the other hand, can’t seem to remember to not rub my eyes after cutting a cayenne pepper. Good thing I don’t use a lot of acids in my cooking. NMRs also seem to be the only mammal that can’t control its body temperature. And now it turns out that NMRs don’t get cancer. The trick, as it turns out, is a sugar molecule called hyaluronan. This sugar is excreted by cells as part of the extracellular matrix, which gives tissues their shape and makes our skin elastic, which is why hyaluronan is already used as an anti-wrinkling therapy. NMRs have very elastic skin thanks to large amounts of long chains of hyaluronans. These long molecules form tight cages around cells, stopping cells from replicating without passing all the proper checkpoints. Consequently, these long hyaluronans stop pre-cancerous cells from overproliferation, hence NMRs don’t develop cancer. Unless you block the production of these hyaluronans of course, which researcher have done with NMR cells in a dish. These cells did start showing cancerous treats and moreover, when implanted in mice, led to tumour development.
It should be noted that this may not be the only mechanism by which NMRs avoid developing cancer. It is more than possible that other adaptations to underground life and the development of thick skin against all the insults they get for their looks, have led to tumour-suppressing powers.
An example of this can be seen in another rodent: the slightly more visually appealing blind mole rat (Spalax spp), let’s call them BMRs. BMRs can live for over 20 years, and do not develop cancers. It is thought to be due thanks to genetic adaptations to hypoxia, caused by low oxygen levels in poorly ventilated underground tunnels (Who taught these moles how to dig?)
BMR cells commit suicide through the process of necrosis rather than apoptosis (the usual method of cell suicide). Research suggests that a high release of interferon-beta, usually an immune response to viruses, limits overproliferation. This interferon-beta is released by abnormal cells, triggering necrosis in themselves and their close neighbours, and therefore suppresses tumour growth.
Again, this is most probably not the only mechanism, especially because the research in question has been disputed and could not be reproduced in vivo. However, it is feasible that evolutionary adaptations to a low-oxygen environment have provided BMRs with mechanisms to avoid cancer.
Scaling it up a bit, we come to something known as Peto’s Paradox.This states that larger animals should have more risk of developing cancer. Assuming all cells are pretty much the same size (which they are) and all cells have an equal chance of getting a mutation that would lead to cancer, animals with more cells should get more cancer. The paradox: this is not true.
Within humans, it has been shown that taller people have a higher risk (almost 20%) of getting cancer. This could be the having more cells thing, but could also be linked to growth hormones: the same processes that lead to body growth are involved in tumour growth. Luckily, six foot me shouldn’t get too worried; taller people are in general healthier (a healthy childhood leads to tallness) and other cancer risk factors weigh through more than height. Smoking, obesity, and poor diet increase the chance of developing cancer, so stay off the cigarets and deep fried mars bars and I should be okay.
So Peto is not so much a paradox for humans, but if we look further, it is. As an example, not only are mice inexplicable terrifying to elephants, they also develop more cancer. More reason for the elephants not to be scared, stick it out for less than 4 years and the mouse will have probably died of cancer anyway. One possible explanation is that some animals, such as the giant elephant and some even gianter whales, have more copies of the p53 gene. p53 is a pretty famous tumour suppressor and is often mutated in cancer. When a cell’s DNA gets damaged, p53 steps in and prevents the cell from dividing and passing on the mutation to the next generation. If the cell cannot repair the DNA damage, this sets off a cue for apoptosis (programmed cell suicide) to prevent mutations from turning into cancer. Having more copies of this gene means the risk of all copies being mutated is lower. So elephants can have a few defective p53s, but still enough working copies to prevent cancer development.
But not dying of cancer does not necessarily render you immortal. There are many biological processes that are involved in aging. One process is the shortening of chromosomes at each cell division. To protect genetic material, the end of chromosomes consist of a region of repetitive DNA sequences called telomeres. As cells divide, these telomeres shrink until they are too short, leading to the cells stopping multiplication or dying. To repair shortened telomeres, cells have a protein called telomerase. Most vertebrates stop producing this protein as an adult, but some animals keep it indefinitely, leading to the popular belief that they – let’s take lobsters for this example – are immortal.
Side note, lobsters are not immortal. While they are able to repair their DNA up until their old age (over 40 years), they typically die from an extreme moult. Moulting is the process of shedding their shell as they grow, preventing it from getting too tight but also repairing any damage that might have occurred. However, the larger the lobster, the larger the shell and the more energy necessary to go through the moulting. Eventually, an old lobster will die from exhaustion of this process, or they will not even bother and die from damage or infection.
Not to take away that this telomerase thing does allow them to get pretty old, though.
Maybe someday soon we can learn from these animals to tackle cancer and aging. Maybe there are other animals that have evolved to do even more amazing non-aging things, but I have not mentioned them because of, well, my limited time in this world.
A few days ago, the Dundonian police made an unusual arrest: a chicken. She had been terrorising East Marketgate’s traffic by performing her own version of a very well-known chicken related joke [I’m not sure anyone knows the actual punch line though]. This caused major distractions to passing drivers and what I presume was a “viewing traffic jam”. [Google translate tells me “rubbernecking” is the correct translation of the work “kijkfile”, but I don’t quite believe it; I basically mean cars slowing down because their drivers want to look at the spectacle, resulting in congestion.]
The police arrested the chicken in their very own headless chicken manner. Twitter tells me this was hilarious to watch and possibly led to more VTJ. The chicken is still in custody, for all I know, until someone claims her back. The police promise to be taking very good care of her – maybe so she would provide them with omelette ingredients – and has placed a lost-and-found post on facebook.
For me, the best part of this story is that I found out thanks to my friend, who lives on the other side of the channel and read the story this morning in Metro during her daily commute. This Dundonian chicken has reached international news.