Prologue - breast cancer metastasis

This entry is a follow-up to "Prologue - the metastacizing cell". Here, I will reveal my second storyboard idea (Figure 1) for the beginning for my animation (although this idea was actually on the first ideas that I came up with a couple of months ago).

While the previous idea of "the metastacizing cell" would be very science heavy, "breast cancer metastasis" will be much lighter. This latter idea will define metastasis, and talk about etiology, of risk and prevalence. At the moment, the former is geared towards the graduate/science community, and the latter is geared towards a patient audience.

FIGURE 1

Figure 1 shows two column of panels. The one on the left, "Breast Cancer Metastasis", will play out like this... The scene will start from black to reveal a faint silhouette of a woman. The camera will be zoomed in quite close to the body just above the level of the breast where her hands will be held. Very faint lights will play over the surface of the body so that there will be undulating light and shadows, and every so often, it will fade to near black. (The best way to describe the feel is that its very much like the intro to a 007 movie, but without the sexual overtones.)

The camera will continue to pan downwards. The outline of the body, remember, will be just barely discernible. So, once at the level of the femur, the undulating shadows will take the shape of trabecular bone. This is how I intend to transition into the bone marrow where the main story will take place.

The narration of this piece will likely commence along these lines:

A metastasis if a malignant development at a secondary site apart from its origin. For example, patients suffering from cancers of the lungs and prostate have a chance of developing a metastatic tumour of 50% or higher. Breast cancer patients have an 80% chance of metastasis. And, the most common site of breast cancer metastasis is in bone, such at that of the thigh. A tumour implanted here will result in one of the most painful conditions a patient may experience.

The column of panels seen on the right of Figure 1, entitled "Metastacizing Cell", shows the earlier draft of what became the video clip shown in "Prologue - the metastacizing cell". The really important thing I want to point out about this strip is that, similar to the left column, the prologue scene will be like a film noir, with a black background, and a strong cast light. At the end of the scene, the background will fade in to reveal the metastatic cell within the bone marrow.

Metastasis question...

Currently, I'm focusing the prologue or introductory part of my animation. As I have mentioned, I currently have two ideas - actually three, but the third idea is merely a combination of the first two - for the introduction.

I'm going to talk about the first one (see "Prologue - the metastacizing cell").

First, in brief, these are the major steps of metastasis: 1) Break away from primary tumour mass. 2) Break through extracellular matrix and extravasate into the blood vessel. 3) Travel in the circulatory system without being killed by hungry immune cells. 4) If going to bone, exit blood vessel from sinusoidal vessels (and break away extracellular matrix again if need be?). 5) Implantation!

What I though was very interesting about the current research was that the metastacizing mass was described as traveling as an embolus consisting of more than a few tumour cells (Mundy 2002). That is, a metastasis travels as a multicellular lump. First off all, I thought, "Well, that means I have to change that last clip I posted!" (Again, see "Prologue - the metastacizing cell".) But then a major question popped up.

So... QUESTION, HOW does the metastasis extravasate? Current literature explains that the tumour cells enter the circulation by accessing the vessels they themselves created through angiogenesis (Kozlow & Guise 2005). But if they're entering through the capillaries which they've created, how do they fit? Capillaries are usually so small that RBCs how to stack up to squeeze through!

Understandably, this is a pathological angio, so I would assume that the vessels are structured differently. But even so... I find it puzzling. Especially since the literature says that they travel in aggregates of many cells. Do these cancer cells extravasate individually, or in file, out into the capillaries. And, is it only in larger vessels that they join together and form the embolus?

Or do they extravasate as a single unit...?

Here is a sample visual (Illustration 1) of tumour extravasation from a website that Louis kindly showed me (Reflexion). Here we see them... sort of entering the vessel where the endothelial cells are absent. Other visuals on this process show: the same thing seen here, single cell extravasating a through an organized endothelial barrier, or the extravasation step is simply absent.

Illustration 1. Taken from Reflexion, Université de Liège.

I will have to do some research on angiogenesis...

Reflexions, Université de Liège. "SIBLINGs, cancer's multifonctional weapons." http:reflexions.ulg.ac.be/cms/c_15009/siblings-cancer-s-multifonctional-weapons?part=1.

Prologue - the metastasizing cell

So, I came up with a potential prologue/intro to my story/animation. The narration will describe in general the how cancer cells metastasize to a secondary site.

The way I see the cancer cell moving is sort of like tumble weed. There will be spot lighting. So, dark ominous backgroung, lonely lit cell casting dark shadows. It will be a 3D rendered cell that rolls - as such migratory cells do - along this highway, jumping across hurdles and avoiding dangerous macrophages. Think old 2D video games where there's only one direction to move!

(Another idea is to have a rolling background. Sorta like a scene-scape that plays - in a vertical fashion - as its own movie behind the rolling cell. I will explain this more later!)

RANK Ligand

Figures 1 & 2 are just some quick sketches that I made of the extracellular domain of the RANK ligand. It's expressed on the surface of T-cells, stromal cells, and osteoblasts, and they are responsible for initiating osteoclastogenesis by binding to the receptor RANK found on monocytic precursors.

These drawings are based off the structural models found on the protein databank.

Figure 1

Figure 2

The axes concept

(Note: At the time of this post, and the previous two as well, it has already been decided that for the final project, this "Axes Concept" will not be incorporated. Such an undertaking, unfortunately, would not be feasible in this research course... However, I would still like to take the time in this post to explain my original ideas.)

As in my previous post, I ended by saying we could "visualize a multidimensional process in multiple dimensions." This statement lies at the core of the AXES CONCEPT.

In order for the Axes Concept to work, the scientific or biological process must be able to be broken down into various components. A string of select components must be able to form a continuum, a progression of one state to another. These strings of components may then be identified as part of one of three progression categories.

EXAMPLE, our biological process is bone cancer. The components are singular events such as: RANK binding to RANK-L, osteoclastogenesis, bone dissolution and resorption, decreased pH. A string ties these singular events together as in these two cases: a) RANK binding to RANK-L, osteoclastogenesis, bone dissolution and resorption, decreased pH; b) bone dissolution and resorption, thinned trabeculae, micro/macro fractures, femur deformation. These two strings can then be understood as being part of two progressions of events: first, as a) a temporal progression, from normal to pathological; and as b) a scalar progression, from a microscopic/cellular level to a gross anatomical level.

Figure 1 visualizes this concept. Each sphere  represents one singular event of component. A string of components would then be a series of spheres along an axis. An axis would represent a progression. Different hues/colours represent different anatomy parts; its axis represents locational change. The brightness of the colour (as seen in the vertical axis) would represent temporal change (light being norma, dark being pathological). Finally, the change in sizes (as shown along the axis with the small to large blue spheres) would represent scalar states. (Note that naturally each axis would be finite.)

FIGURE 1

By organizing and molding the topic of bone cancer pain onto an three-dimensional graph, it was my intention to give students a degree of interactivity, to allow them to choose which components or progressions of events that they wanted to study. As I have mentioned previously, animations are more adept at transferring knowledge that was simple and linear in format (Moreno & Mayer 2002; Tversky & Morrison 2002). As a response, the Axes Concept was a solution that allowed the process to be learnt in customizable stages.

On the functionality of the product... I imagine that viewers could opt to view singular components. They could metaphorically choose to view a particular sphere which would be a short clip. Or, they could view a string of events (a series of spheres).

To choose a string, the viewer would select an intersection of two axes. The remaining axis would dictate the type of progression that they would actually see. For example, in the first string shown in Figure 2, the two constant axes are temporal (the slightly darkened colour may mean later during the tumour's life) and locational (let's say green represents the marrow cavity). The variable axis is the scalar one. The string or series could theoretically include the following video clips: ongoing bone dissolution and resorption, thinned trabeculae, bone marrow replaced with tumour mass, damage to mechanonociceptors from mass, micro/macro fractures, femur deformation.

FIGURE 2

Similarly, the second series of clips in Figure 2 could be of temporal change located at yellow, at a tissue level. The third series could be of extracellular events occurring at various locations in the later stages of the cancer.

On creating dimensions...

Here, I will attempt to propose a solution to the problem of visualizing a multidimensional process. Hopefully, this may be applicable to more than just my own MRP, wherein I must attempt to visualize a multidimensional pathology, and may be applicable to other complex scientific knowledge.

In my own case, I am dealing with a pathological process that involves a multitude of locales. These locales may first be identified by their anatomical location. Secondly, they may be identified by their scale, in the sense that the pathology can be observed macroscopically, microscopically, and anywhere in between. Finally, they be pinpointed in time, starting from a normal to a pathological state and ending in the eradication of pathology or the termination of the patient.

By breaking down the pathology of bone cancer pain into these locales, I came to realize that I could organize them into 3 distinct categories. As hinted in the previous paragraph, the categories are: scale, location, and time.

Now, to backtrack a little... It was during the process of breaking down the components of bone cancer pain that I was trying to find a way to present all the material in a manner than didn't overwhelm the viewer (see previous post). I had been toying with the idea of interactivity and scene selection, so that the viewer may decide what they wanted to see. Essentially, the idea was to break down the content into clips - like chapters in a book - so that they could learn in segments.

However, this chapters-in-a-book idea was not very appealing... I mean... it's like a textbook... with chapters. The end product would not be all that different from having a a pause/play button... But, then, out of nowhere I got an idea.

Recall that the scientific content could be broken down into locales, and these locales could be organized into three categories: time, scale, location. And with each category, the locales could be arranged in a linear order. With time, the locales could be arranged from before to after. With scale, the locales could be arrange from gross to microscopic. With location, the locales could be arranged from peripheral or central.

Now consider this. Visualize a multidimensional process in multiple dimensions. That is, why not visualize time, scale and location as if they were each their own axis!

(Explanation coming next.)

Round table 2

In attendence: Philippe, and I

I had the pleasure of meeting Dr. Philippe Sarret and a couple of students from his lab during the M2C pain summer camp. Over a cup of leek soup, plate of salmon, and sugar ridden desert, we talked about an interesting idea...

As with many pathologies, the physiology is only a small part of the picture. In order to gain a full understanding of the topic, one needs to understand the etiology, pathology, anatomy (both gross and microscopic), intracellular biomolecular chemistry, etc. In our case, in bone cancer pain, we must deal with two pathologies, that of the cancer, and that of pain.

During my readings, I came to realize that animations may be very useful in understanding scientific processes in the way that they laid out the various elements into a logical, chronological story (Mayer and Moreno, 2002). Animations are successful in this task because it helps the viewer make connections between the various components of the story; it is especially successful in telling processes with strong before and after scenarios. Unfortunately animations encounter pitfalls when the process becomes too complicated or multidimensional. At the point when the animation is too long or too complicated, the viewer can no longer retain the information presented, and thus, they can no longer make associations between the various components of the scientific process at hand.

This problem was brought up during my conversation with Dr. Sarret. And, I have decided to propose a possible solution to this problem... (see next post)