Recreating our biology from inside-out

Can scientists build a human body from scratch?

Our ever-expanding knowledge of human biology has allowed researchers to create a wide range of disease models from one-cell type cultures, or monocultures, to genetically engineered mouse systems. Selecting a suitable model remains one of the biggest challenges for researchers today, particularly as we often recognise gaps in our knowledge as we begin to unravel the true complexity of human disease. Additionally, ethical considerations continue to play a large part in medical research; performing studies on human subjects requires extensive preclinical data to ensure patient safety. However, it’s vital that scientists aim to establish the true ‘translatability’ of experimental data. 

With that in mind, it is worth considering whether biotechnology could recreate the systems of the human body from scratch If scientists succeed, would multiple models or complex data interpretation still be required to advance our understanding of infection biology, genetic disorders, cancer or neuroscience? Here is what we know.

Human samples – often referred to as resections or biopsies – continue to be the most accurate model of disease. However, researchers are often limited to small sections of the resected tissue, with the rest (often) being kept by a pathology department within the hospital. In addition, fresh samples are sometimes essential for researchers to produce biologically-relevant data. There is little point in attempting to perform a live-cell imaging experiment, if the cells have been frozen – and may therefore be much less viable.

No aspects of our biology works in isolation and therefore scientists are challenged to consider the inherent surrounding or the microenvironment of each organ, or tissue, when drawing conclusions about the findings from a procedure. So, how could scientists ‘preserve’ tissue in a ‘natural’ state? Recent studies have suggested that researchers may be able to mimic, or mirror, our organs, in their physiological state – whilst also controlling features such as blood flow or oxygen transport. In this article, Iris and myself will discuss the current research and utility of two novel approaches to modelling disease: organoids, or mini-organs, and organoids-on-a-chip, using the colon and lung, as prime examples. 

Organoids, or mini-organs, are 3D structures that can be grown from many cell types and allow scientists to re-create a highly-specific model of an individual’s disease. Organoids are derived, or created, by breaking down, or digesting a small amount of the patient’s own tissue and culturing these cells in a net-like structure, or scaffold, known as Matrigel. This allows cells to move towards one another, which occurs due to chemical signals that are present in the microenvironment, or culture medium (as seen in Figure 1). 

Figure 1 | Deriving an organoid from a tissue biopsy. Cells are grown in a net-like structure and subsequently used for drug screening to guide tailored treatment to patients | 
Creative Commons Law applies. Image created by author(s), using BioRender.

One of the many hopes for organoid technology is that it may accelerate the field of personalised medicine, allowing doctors to give the most effective treatments to each patient, tailoring their approach to the individual’s biology.

(An) organoid acts like an avatar for the patient [ref.]

Hans Clever, a professor in Molecular Genetics at Hubrecht Institute / Utrecht University (NL)
A world-leading expert in organoid-based systems

Although organoids may appear to be a robust model at first glance, fellow scientists have noted that that this system lacks the necessary control of biochemical features; these include variation in blood flow, which may otherwise be provided by micro-physiological systems, such as organoids-on-a-chip (sometimes referred to an organs-on-a-chip).

Whilst organoids exploit the intrinsic developmental programs and use the ‘self-organization potential’ of stem cells, organoids-on-a-chip, allow scientists to precisely engineer constructs based on our knowledge of human anatomy.

Figure 2 | Recreating an organ on a chip. The identified essential components, such as epithelial and endothelial cell layer, are recreated in a closed system | 
Creative Commons Law applies. Image created by author(s), using BioRender

To create an organ-on-a-chip, researchers must first understand the anatomy of the target organ and identify the most essential components for proper function (as seen in Figure 2). One of the major challenges of creating organ-on-a-chip, is that scientists are yet to fill the knowledge gaps in how organs are formed during embryonic development, known as organogenesis

Another challenge that this model presents is how best to model any dynamic changes within this system, as cellular development is dependent upon their exposure to different molecules; scientists must therefore mimic the fluid movement within our body in order to obtain an accurate model. However, the idea is that such knowledge would enable the basic design of a cell culture device, which might consist of multiple interconnected chambers that can be controlled individually. This approach has already allowed researchers to investigate highly specific cell-cell interactions and alter the microenvironment, simulating a dynamic range of physiological conditions.

In summary, organs-on-a-chip lack the spontaneity of organogenesis and organoids are missing the control of man-made systems. That’s why researchers are trying to combine the best features of each approach to generate more versatile and predictive models. However, the clinical utilization still remains a distant goal due to the low efficiency and safety concerns. 

Organoid-based approaches are currently being investigated as a highly suitable strategy for direct translation of fundamental science research into the clinic and scientists have already established a heart-lung-liver organoid-on-a-chip that is interconnected with a pump. This model has been used to test systematic drug effects on multiple organs at the same time – an important aspect of evaluating drug toxicity, or toxicology. Scientists hypothesise that, by combining several organoid-on-a-chip systems into one, they can study aspects of the complex biology such as metabolism for example, which is known to involve the kidney, liver and gut. 

Although these technologies remains in their infancy, some researchers have begun envisioning a whole ‘body-on-a-chip’, suggesting that it is not unreasonable to imagine future scientists – both biologists and engineers – building a model of the human body from scratch!

However, the truth is that this outcome remains quite far down the line.

For now, the hope is that one day, these systems will be used instead of animal models – particularly as organoids-on-a-chip have shown promising applications within the multiple stages of drug discovery and could pave the way for creating highly accurate human disease models.

From the co-author:

Hi! My name is Iris and I am a Master’s Degree student at IMC Krems, Austria, currently doing an exchange year at Linköping University, Sweden. As I am in my last year I am now starting to write my final thesis, which investigates the epithelial interaction of the human gut with cells of the immune system. Apart from this, I love to engage with other science Instagrammers on the platform to gain some insights into the world of Science Communication. This is also where I met Holly.” – Iris (@science.with.iris on Instagram)

Feature Photo by Robina Weermeijer on Unsplash

All primary references are available on request

Published by Holly Leslie

Full-time Cancer Researcher + Freelance Science Writer | MRes, BSc | Since discovering my passion for science writing during my final year of undergraduate study, I've written articles for University newspapers, The Gaudie and Redbrick and two Science magazines, Wonk! and the Glasgow Insight to Science and Technology (GIST)

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