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Growing up in a university biology programme, things had a certain order: we biologists kept to our corner of the sandbox, playing only occasionally with the chemists and even less with the physicists.  Evenings were another matter, but that falls within the remit of other sites on these here internets. This pedagogically imposed segregation may have been a necessary evil to ensure that burgeoning scientists remained focused while learning the fundamentals to their respective disciplines. And while I’m sure we could argue the pros and cons to this approach in a teaching-then-and-now sense, I can attest to the fact that it has created cohort after cohort of scientists who still adhere to these artificial boundaries, often to the detriment of progress.

So people eventually start to think next-gen; realising that working together helps, and not just for technological progression. INTERDISCIPLINARY becomes a buzz word and suddenly university departments start springing up all over the place; the bastard children of tawdry scientific consorts between pairs of specialties; Bio-Engineers, Molecular-Anthropologists, Mecahno-Compu-Socio-Biologists—oh my! And yes, I know those were all bio-heavy. But come on, this is real science I’m talking about here! [Oh how we still play with each other!]  Most major granting bodies have special categories for partnerships between biology and other facets of science. There I go again. It’s an artificial distinction.

Think of it this way: it’s all about scale.  Physics generally governs the realms that study the interactions of the individual components of matter and energy at the subatomic level. Astrophysicist try to understand how these same principles then apply across scales that describe the cosmos.  As subatomic particles associate to generate atoms of the various elements, we have chemistry.  Atoms begin to interact with each other, interact with energy, and organise into complex structures.  After a sufficient amount of certain types of complexity, you’ll enter the realm of living things; biology. At the moment, I find myself at the nexus of mechanics (physics and engineering) and biology, or mechanobiology.  More specifically, mechanobiology deals with how living systems respond to mechanical forces.

I remember sitting in a talk at Wayne State University given by Neal Pellis when he still worked for NASA about biological experiments being carried out in zero gravity by NASA astronauts thinking, If embryos don’t have gravity, how do they orient themselves; head vs. feet, front vs. back?  The merits of the question itself are less important, but it was probably one of the first times I can remember trying to reconcile biology in the larger context of physics. [SCIENCE BOUNDARY KLAXON!]  Positional information in embryonic development is crucial. This is how embryos can start to build themselves from a single cell.  They form a basic pattern, based often on spacial cues from their environment, in our case a uterus, and build from that basic pattern.  Through migration and interactions with other layers of cells and tissues, cells begin to specify, axes form; front becomes different from back.  But there it is: migration. Cells move. Cells don’t just react to forces, cells generate forces.  [SCIENCE BOUNDARY KLAXON!] Dammit, wish I’d listened more during physics!

My brain began to dole out interdisciplinary olive-branches in ernest when I was in Cambridge, as our group often waxed biophysical, trying to understand how physical forces impacted developing embryos. A friend of mine worked on understanding the rhythm of flows in fluid inside the a fertilised egg. It turns out that these rhythms are established from the moment of fertilisation.  Sperm entry into the egg triggers calcium fluctuations that cause contractions in a network of proteins that force the fluid in the cell, the cytoplasm, to start to flow in sync with the calcium spikes. Moreover, these flows can serve as good predictors of embryo health for mammalian IVF embryos.

But it wasn’t until I came to QM that I started to address some of these questions myself.  I am, at heart, a developmental biologist, so one of the questions I was curious about was how it is that stem cells respond to mechanical forces such as gravity or the pull from a neighbouring cell?  Also, at what point do those mechanical signals start to play a role  in the journey from stem cell to bone, our chief load-bearing tissue in the body, for example.  This is a particularly important question when you consider it in the context of regenerative medicine, where the goal is ultimately starting with a patient cell, reprogramming it into an embryonic-like state, and using that as a therapeutic base to treat disease.  If the patient donates their own cells, there are no issues with rejection.  Currently, though we have the technology to reprogram adult cells into a more embryonic state, theoretically making it possible to create every cell type in the body, we lack the fine control in necessary to coax stem cells into certain fates, such that if we have millions of cells in a petri dish, for example, only a relatively small fraction do what we tell them to do, which raises all sorts of flags about their safety.  This is where understanding how cells respond to all sorts of signals, whether they’re mechanical or chemical, becomes important.

Ultimately what defines one cell type from another is down to its function; usually dictated by the sorts of genes that are turned on, or expressed,  in a cell.  Genes live in the nucleus of the cell. So the general path of information starts with an external (extra-cellular) signal that is transmitted (transduced), that results in some sort of change in what the cell is doing genetically, in the nucleus. A lot of attention has been directed at understanding how this process works biochemically for decades; with molecules binding receptors on the external side of the cell membrane that then trigger signalling cascades that result in a change it he pattern of genes a cell expresses.  As it turns out, mechanical forces may be processed in a similar manner; originating on the outside of the cell and being transduced through the cytoplasm to the nucleus, altering gene expression. This was the subject matter of a recent review that I had the pleasure of co-authoring.

Annual Reviews Biomedical Engineering 14: Mechanical Regulation of Nuclear Structure and Function.

And as a bit of shamless self promotion, what follows are excerpts from the historical section, and one of my figures of the nucleus.  Anyone who’d like a full reprint, please contact me.

Conceptually, the idea that development and differentiation are shaped by extrinsic (mechanical) forces is ancient. Aristotle thought that embryonic development was in part directed by the locomotive component of the soul. This so-called Aristotelian soul differed from the more traditional or spiritual concept of a soul in that it is generated through the (physical) mixing of male and female semen (9), producing a teleological driving force that gradually gestates that individual organism to its final form (10). Teleological reasoning such as this persisted for millennia. However, over time, the notion of the Aristotelian soul as a driving force was either replaced by a divine, perfecting force (11) or obviated altogether by the notion that organisms were preformed and grew with no need for ontological development or differentiation (10). In the mid-1800s, Darwin published his theory describing evolution as a slow and gradual process of descent with modification, resulting in stochastic variability capable of conferring selectable (morphological) advantages to promote survival or increased reproductive fitness of an individual. He included many observations of embryos, as he saw them as “picture[s], more or less obscured, of the common parent-form of each great class of animals” (12, p. 450). Along with this, and more central to this work, he was also among the first to promote a movement away from teleological thinking, suggesting that evolution (and embryology) need not be a process seeking to perfect a morphology, per se (11). This point was later elaborated on by Wilhelm Roux and Julius Wolff (13), in Germany, toward the end of the century.

Wolff was an orthopedic surgeon who conducted research into how the structure of bones changed with alteration of function owing to either growth or pathology. His ideas followed from those of Roux; namely, he maintained that life has two periods, an embryonic one characterized by trophic organ growth and differentiation, and an adult one in which growth and remodeling occurs only when stimulated by healing or (cellular) turnover (13). These stimuli, which Roux collectively referred to as developmental mechanics (11), had an overall effect on tissues irrespective of life period, resulting in their remodeling. Wolff postulated that there was a causal relationship between the physical forces acting on bones and the observed changes to both gross morphology and internal architecture. In particular, he predicted that remodeling of bone trabeculae followed the mathematical trajectories of the forces acting on them. He also went a step further, suggesting that these same mechanical signals could provide one plausible mechanism for Darwin’s theory of natural selection (13). Since the publication of Wolff ’s work, the accuracy of some of his mathematical predictions has been called into question (reviewed in 14). Another common criticism is that his theory cannot be considered a law because other bones and tissues do not exhibit the universality sufficient to explain the phenomena he described in cancellous bone. Despite these detractions, his observations were made well in advance of the discovery of radiography and modern tissue biology techniques. Wolff ’s work is thus deservedly recognized for its pioneering contributions to the burgeoning fields of orthopedics and tissue mechanobiology.

Figure 1, Mechanical Regulation of Nuclear Structure and Function, Annual Reviews Biomedical Engineering 14

Figure 1: The archetypal SUN-KASH domain association in the LINC complex. (a) The LINC complex is typified by an association between SUN-domain proteins ( yellow) on the inner nuclear membrane and KASH-domain proteins ( green, blue, and orange) on the outer nuclear membrane. KASH-domain proteins form a functional link with the networks of cytoplasmic intermediate filaments, microtubules, and actin microfilaments, which compose the cytoskeleton. SUN-domain proteins bind to the nuclear lamina, a network of intermediate filaments composed of varying isoforms of A- and B-type lamins, LAPs, and LRs. The lamina also serves as a tethering point for the genome, with associations reported among various lamins, LAPs, and LRs. (b) KASH domains associate with SUN domains in the perinuclear space, and this association maintains the architecture of the nuclear envelope. SUN proteins can associate promiscuously with KASH proteins and can also form homo- and heterodimers with other SUN proteins. (c) Two competing models explain the 3D organization of CTs in the interphase nucleus. The CT-IC model posits that a largely DNA-free compartment of contiguous spaces between adjacent CTs exists. The second model, known as the intermingling model, maintains that whereas CTs occupy nonrandom spaces in the interphase nucleus, there is a large amount of intermingling of the chromatin between adjacent CTs. Abbreviations: CT, chromosome territory; IC, interchromosomal compartment; KASH, Klarsicht/ANC-1/Syne-1 homology; LAP, lamin-associated protein; LINC, linker of the nucleoskeleton and cytoskeleton; LR, lamin receptor; NPC, nuclear pore complex;SUN, Sad1 and UNC84.

June 2017
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