Imagine the possibilities of mimicking human biology in a petri-dish : as simple as few neurons firing in a mini-brain, or as complex as the complete circulatory system. The potential applications of such a technology would be quite fascinating, at least from a medical point of view. We would be able to answer questions related to the effects of external agents on humans: Can another coronavirus cause a pandemic in the future? Or can a medicine cause any harmful side effect? We would also be able to mimic diseases and find suitable treatments by testing different drugs. We may even be able to understand how different organs are developed in a fetus starting from just a few cells.
Now let us take this idea to the next level and imagine if it were possible to mimic every human from just a small sample of cells from their body. You may already be aware that each one of us is slightly different at a genetic level (which is why we have different eye colors). But did you know that genetic differences between people can cause diseases to be genetically unique to us? (Study). Cancer, Alzheimer’s, multiple sclerosis, lactose intolerance are all examples of diseases that are considered to have a high genetic variability between individuals. Treatment of such diseases is not possible with any single drug as is the case with other diseases like malaria or typhoid. With this new technology, we would not only be able to mimic every individual, but also test and ‘personalize’ drugs for diseases that are unique to those people.
One may think of other interesting applications such as organ implants, or lab grown meat, but we will restrict ourselves to biology that can be modelled ‘on a chip’ for the purpose of this article. Biology and engineering have together made it possible to capture simple biological functions in miniaturized systems, with a small biological sample. These technologies are called ‘organoids’ or ‘organs-on-a-chip’ and allow for generating personalized organs. Following paragraphs contain few basics of this technology, some key advantages of using them, and a couple of interesting examples. Briefly, we will also look at how these technologies are currently being used to tackle COVID-19.
What is organ-on-a-chip technology?
When cells are cultured (meaning cell are grown/expanded) on a small chip (generally few microns to few centimeters) to form a tissue in 3-dimensions, such that it replicates important functions of an organ, it is referred to as organ-on-a-chip. Currently used cell culturing in biology labs only form the tissue in 2-dimensions and are hence not able to accurately represent human biology (after all, humans exist in 3D not 2D!; also see box below). Organ-on-a-chip technology utilizes specially designed biomaterials that are quite like the matrix that keeps the cells in our body together. These biomaterials allow the cells to form complex 3D structures like those found in the body.
Majority of our organs are connected through blood vessels, nerves, and other systems, so that they can exchange important biochemicals for proper functioning. To mimic this system, complex organs-on-a-chip are dynamic and allow continuous flow of biological chemicals in and out of the artificial tissue. These models use a system of fluid channels (as shown with blue and orange channels in figure below), valves and flow controllers (not shown in figure above), to allow controlled interaction of different subsystems.
Researchers have developed a variety of organ-on-a-chip models. Some of them are complex and mimic a single organ function, such as the breathing lung model for modelling interaction between air and alveolar sacs of the lung, the contracting-expanding muscle model for modeling the beating of heart muscles, and immune organ models (lymph nodes, bone marrow) for modeling immune response to external agents. Some others are used to mimic diseases, such as the cancerous growth of cells in solid tumor tissue model (for breast, brain, colon, kidney, liver, pancreatic cancers). Yet some other models mimic specific functions, such as skin models for studying skin’s response to applied chemicals.
‘Lung-on-a-chip’ developed by researchers of the Wyss Institute of Biologically Inspired Engineering at Harvard University (Source)
Breathing lungs and beating hearts - on a chip!
To mimic the functioning of human lungs, a model using cells from the membrane of human lungs has been developed. These cells are embedded on top of a stretchable inorganic material, which is then attached to the middle of a hollow chamber. This hollow chamber has two side chambers that allow for stretching and contraction of the membrane by applying vacuum. This stretching and contraction motion is like what happens in the case of real alveoli in lungs. The membrane can be exposed to blood or blood-like fluid on one side, and air with the desired composition on the other. This complex system allows for recapitulating chemical and biological interactions of the lung cells with air and blood that would not be possible in the usual 2D cultures.
Working principle of lung-on-a-chip (Source)
Image by: Timothy.ruban / CC BY-SA (https://creativecommons.org/licenses/by-sa/4.0)
A heart-on-a-chip utilizes a different microfluidic structure to model functioning of the human heart. Like many other on-chip devices, the microchannels are constructed from a polymeric compound called polydimethylsiloxane (PDMS). These channels are then coated with a compound that supports cell attachment and growth, and finally with cells that mimic heart muscles. They are supplemented with appropriate food for the cells containing different chemicals such as amino acids, sugars, salts, and some important biomolecules. See how heart cells beat normally, and how they start beating differently when they are supplied with drugs in the video below. This model can accurately predict the response of heart cells when the same drug is injected in humans. Thus, by using feedback from this model, the drug can be redesigned to get better effects.
Watch the ‘beating’ heart cells on a chip (link) developed by Kevin Healy Lab (UC Berkeley).
Advantages of organ-on-a-chip technology
There are few main reasons why organ-on-a-chip technology has already captured significant scientific and commercial interest.
First, this technology has the potential to replace animals in testing chemicals that need to be introduced directly into humans or which would come in contact with humans. For example, organs-on-a-chip provide an ethical alternative for animal testing to pharmaceuticals industry as well as other industries such as cosmetics and household cleaner industry which currently test their products on animals.
Second, this technology has started a revolution in treatment of diseases. As described before, many diseases are genetically different from person-to-person (even though they may produce similar symptoms). Currently, most of the diseases are treated uniformly. For example, it is believed that a certain chemotherapy drug X works on all patients with breast cancer. In this view of medicine, all human subjects are considered equal (as shown below in the infographic). However, in practice, drug response can vary significantly based on age, sex, personal history, and ancestry. Thus, the currently used chemotherapy drugs often fail to produce lasting results. Organ-on-a-chip models have opened new doorways for managing diseases in a more personalized manner. We can now first create models for individuals, then test a personalized drug Y on these models. If found effective, Y can then be administered in patient.
The traditional one size fits all medicine versus personalized medicine that accounts for individual differences (Source)
Third, it is estimated that organ on a chip models will save somewhere between 66 and 706 million US dollars during a 5 year period between 2018 and 2024 (Study). Currently, it takes around 600 million to 2 billion dollars for a new drug to be put up in the market. Eroom’s law (Moore’s spelled backwards) suggests that the cost to develop a new drug doubles every nine years. Even after spending a lot of money and time, several drugs that pass through the initial 2D culture-based testing as well as animal trials fail during human tests. This failure rate is expected to go down significantly if organ-on-a-chip models are used, thus bringing down the costs associated with drug development.
Supporting drug discovery for COVID-19 and preventing future outbreaks
In the past several months, researchers have raced to find a cure and a vaccine for the novel coronavirus. Organoid technologies (closely related to organ-on-a-chip technology as described above) have played an important role in modeling the effect of coronavirus on different organs of the body (Study). Many researchers have observed that it is better to use this technology as compared to animal models or 2D cultures because some drugs that work in animals have no effect in humans (Article). Lung models that have been established before are now used to conduct studies related to SARS-CoV-2 (Study, Article)
In another type of study, researchers modeled the effect of SARS-CoV-2 in human blood vessel and kidney organoids. They also tested a drug with initial success, that may indeed prevent spread of the virus in these organs and reduce the overall harm caused to body (Study). In yet another study, researchers were able to use cells from bat intestine to generate bat intestinal organoids. The novel coronavirus sustained in these organoids and was used to study the transmission into humans. They were able to sustain viral replication in human intestine organoids, proving that one of the routes of transmission for coronavirus could be through human feces (Study). It was claimed that this approach could be useful in studying other bat viruses that may find their way to humans and cause fatal infections.
What does the future hold?
Scientists continue to add complexity to organ-on-a-chip model to mimic human biology more closely. The latest organ-on-a-chip systems are already able to model complex biological functions that involve multiple organ systems. We may still be far from a complete miniaturized human-on-a-chip, but it is not difficult to imagine a sometime soon in the future when organ-on-a-chip technologies will save millions of lives. This would all be possible to achieve at a cheaper cost to the patient as the research and development of drugs becomes faster and cheaper.
Acknowledgement
I would sincerely like to thank Charu Mehta, Prachi Pande, Viplove Arora, Aayushi Uberoi and Rachana Agrawal for spending many hours on providing feedback and suggestions to improve the content of this article.
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