The Mechanics of Biology: May the Force Be with You

Tiny forces unlock new insights in the discovery of new drugs for mechanical diseases

The human body operates not only through electrical and chemical signals but also through mechanical cues. Although cells look static under a microscope, they are dynamic structures, hustling for space in a packed environment. Cells move, change shape, tug, pull, and squeeze against their surroundings and each other, exerting force as they do so. These forces are incredibly small — on the scale of piconewtons, or roughly one-billionth of the weight of a paperclip. But they can have profound biological impact.

The idea that mechanical forces affect cellular function was put forth a century ago by Scottish scientist Sir D'Arcy Thompson in his seminal work On Growth and Form ¹.

Cells utilize specialized force-sensing proteins such as mechanically activated ion channels to effectively convert mechanical forces into biological activities ranging from cell proliferation and differentiation to tissue development. This process is generally termed mechanotranduction.

What happens when cellular mechanical systems fail?

It is emerging that mechanotranduction affects almost all cellular processes, from cell-cell and cell-extracellular matrix interaction to cytoskeletal architecture and gene expression ². Wound healing, contraction of heart cells or a simple act of breathing, focusing our eyes and childbirth, all are indirectly related to mechanotranduction. In this manner, physical forces provide a mechanism to propagate signals within and between cells ³.

But what happens when that coordination fails, when our cells stumble, tire, or miss a beat, or forget their routine altogether? What happens when our cellular mechanical systems fail? This disruption in normal mechanical function at the cellular and tissue level can lead to numerous diseases. 

Perhaps the most recognised example is the rhythmic contraction of muscle cells, in particular the cardiovascular system. Cardiovascular conditions such as heart failure arise when heart cells lose their rhythm, failing to contract and relax as required. Asthma, a respiratory condition, can be traced back to the smooth muscle cells lining our airways contracting too tightly and crowding too closely.

According to the World Health Organization, 4 out of 5 CVD deaths, are attributable to heart attacks and strokes. Vascular smooth muscle cells comprise the mechanically active component of the blood vessel wall endowing it with the ability to constrict and dilate. To evaluate the viability of a muscle tissue, it is essential to measure the tissue's contractile performance as well as to control its structure. Accurate contractility data can aid in development of more effective and safer drugs.

Scientists do have tools that make it possible to microscopically measure the forces as cells stretch and relax. However, researchers still struggle to tell apart the true effects of cellular forces and it is still unknown how these processes play out in the complex environment of a living organism. But by combining 'mechanobiology' tools with other measurements of genetic and biochemical activity, researchers can begin to understand how force is translated into function.

Various approaches have been developed to measure mechanical forces, e.g. micro-post array ⁴ magnetic tweezers ⁵, optical tweezers ⁶, atomic force microscopy (AFM) ⁷ and traction force microscopy (TFM) ⁸. However, technological barriers and complexity have traditionally posed challenges that often restrict their use to researchers in engineering or the physical sciences. For example, TFM involves, in large part, detailed calibrations and challenging calculations that are necessary for quantifying contractility. Another significant challenge is that most methods are largely low-throughput and indirect and therefore ill-suited for studying many different conditions or populations simultaneously ⁹. 

Most force-measurement experiments remain time-consuming, which limits their usefulness for applications, such as drug screening, which require parallel analysis of large numbers of cells. Hence, more innovative tools are needed. But how can you replicate these methods so that they are faster, safer, and apply more broadly across diseases? Currently, no suitable tools are offered to quantify contractile forces in a reliable, high-content platform suitable for the pharmaceutical industry ¹⁰. 

Moreover, quantitative contractile strength has been left largely unexplored in drug development, due to a lack of label-free high-throughput screening platforms and quantitative assays ¹¹, ¹².

Drug screening and discovery: The need to consider cellular forces

Such barriers can ultimately impact getting new drugs to patient. There are various reasons for drug failure in the developmental stage including toxicity, adverse effects and inefficacy. An estimated 90% of drugs that emerge from preclinical studies go on to fail in
Phase II or Phase III trials ¹³. These high failure rates can be partially attributed to preclinical experiments poorly predicative of human efficacy and unmanageable toxicity ¹⁴. While the current gold standard methods relevant to the condition may provide more accurate screening results, they are susceptible to producing false positives as cells are continuously influenced by constant chemical and physical interaction with the surrounding microenvironment. 

We hope that drug screening can be improved with the use of human cells of phenotype most relevant to the condition, ideally being derived from patients (representative of the disease stage being targeted), and then cultured in the most (patho)physiologically relevant conditions. This approach is intended to ensure that the assay emulates the biomechanical environment, in the condition to be treated. Ideally, the assay would also embed cell mechanical measurements of deformability, stiffness, and/or contraction, as in many organs and diseases, these cellular changes often constitute the principal endpoint of therapeutic intent.

To address the current challenges and accelerate the drug discovery process our lab at the University of Glasgow has developed ForceBiology, a highly sensitive high-throughput (HTS) in vitro drug screening platform for studying mechanical diseases triggered by abnormal cellular force generation, by measuring contractility as a new drug assessment marker. ForceBiology offers a label-free, quantitative force readout in comparison to standard laboratory tests. The system can mimic in vivo conditions, matching healthy and diseased tissues. This leads to reduction of time, cost and use of animals.

As we venture into this new era of drug discovery and screening, we are poised to harness the full potential of mechanobiology, unlocking its behaviour  for the benefit of patients. Innovative tools like ForceBiology can reduce the number of expensive failures in later stage clinical development, by improving clinical predictability early in the drug discovery process, thus spearheading the movement to bring mechanobiology out of the shadows and into the forefront of cutting-edge drug discovery.

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Nikolaj Gadegaard FRSE, is professor of Biomedical Engineering and Director of Research in the School of Engineering at the University of Glasgow. He has worked at the interface physics, engineering, and biology for more than two decades and is an expert on the use of micro- and nanofabrication technologies for biomedical applications.

Badri L Aekbote, PhD is a Research Associate in the Biomedical division of the School of Engineering at the University of Glasgow. He is an expert in microfabrication and cleanroom technologies with 10+ years of multidisciplinary experience in mechanobiology and plasmonic.