Anthia Maysidue is from the Department of Chemical Engineering and Biotechnology and a member of the BioElectronic System Technology Group. Here, we are sharing her virtual lecture for Cambridge Festival 2021, on ‘Organs-on-Chips.’ Visit here.
‘Organs on chips’ is one of the most innovative and incredibly useful emerging technologies in biomedical research. It can benefit studies of Human Biology, with a particular focus on how this modern technology is shaping our way in practical development. The way we approach drug discovery and development nowadays is an extremely arduous and costly process.
Every year, thousands of potential drugs are screened during the pre-clinical phase till down the most promising ten or maybe twenty drugs, or ‘leads’, as we call them. After thorough testing in pre-clinical models, maybe ten of these are taken forward in the first-in-human trials, during which they are administered to just a handful of patients.
Two to five of these drugs which show promising results in patients are taken forward to larger trials with about a hundred patients, and in the good scenario, two to three drugs will work well enough to go into the late clinical trials with about thousands of patients. This will show if a drug works better than the current or previous treatment in order to be approved and licensed.
Although each step may be very well-designed and each experiment carefully designed, it is clear that some clinical trials are needed to pass new drugs, and their safety and efficacy in humans to be made very high.
One of the major reasons for such high failure rates is the fact that tools that we currently use to screen the molecules before they reach clinical trials have feeble predicting power. In pre-clinical research, the aim is to determine if the drug is safe and effective to use before it can be safely administered to people during human clinical trials. This stage is essential for the human volunteers’ safety in medical research.
What we need to Explore?
Basically, at this stage, we need to learn how the disease works, to identify the kind and amount of drug that can be safely administered to a volunteer and be effective. When we have been developing drugs, we have two tools at our disposal: animal testing and cells in dishes. Cells in dishes do not work as they do in the human body, so they are not predictable. And obviously, animals are not humans. A mouse is not like a human. Although some of the basic bodily processes are similar, other processes immensely differ from humans.
Let’s take the heart as an example. The heart of a mouse beats about 300 to 800 times per minute, and a human heart beats about 70 to 100 times a minute. The heartbeats of a mouse and a human are so different that a potential medicine that may be safe and effective in a mouse is later discovered to be toxic or ineffective in humans. There are also increasing ethical concerns related to the use of animal studies. As you can see, the principle of 3 Rs here is urging for replacement, refinement, and reduction of animals for research. So, the drug development model is broken, and it has created a gap between a good idea in the lab and the first test of a drug in humans that is usually referred the ‘Valley of Death’ in this lecture. This Valley was also created by lack of funding and lack of development, expertise not only on the academic side but also about financial risks on the industry side.
Many ideas cross this gap each year, but the difficulty adds to the time and cost of developing the new medicine. As a result, there has been a worldwide surge to find replacements for preclinical models that will better predict how HUMANS will respond to medication.
What is ‘Organ-on-Chips?
Organ-on-chips has risen as one of the promising technologies enhancing our abilities to translate science into innovative medicines. All the field efforts are focused on how we can get better translational preclinical data and predict how compounds are going to behave in the clinic. So, more compounds will move through clinical development and get approved as medicines to treat patients. Imagine this technology as a bridge over the Valley of Death. This potential sounds amazing, but what exactly is an organ-on-a-chip?
Organs-on-chips are miniature devices that help us, researchers, to recreate aspects of the structure and function of specific organs in the lab. The word ‘chip’ might confuse someone to think that it has something to do with computer chips. No, they’re not computer chips. However, organ-on-chips have a similar size, and they are made using similar methods. Nowadays, we can find them in many shapes and sizes, but they share some common features. They contain human cells and tissues which grow within the chips, which we call chambers.
These are also connected to small pumps, which are specialized to allow fluids to flow through the tunnels between the chambers where the cells grow and provide them with necessary nutrients and gases like oxygen. This flow is even used to mimic the blood flow in our body. Chips also contain sensors that help us monitor and control the chamber’s environment according to the needs of specific cells. Still, it allows us to control doses of therapeutic compounds and show us whether the cells grow healthy and function well. The fluidic flow also allows us to obtain samples for further analysis in the labs.
How the idea of ‘Organ-on-Chips’ works?
In my perspective, organs-on-chips is a new way to mimic human biology. The traditional way of doing so is looking at a single cell or clusters of cells in a dish. Organ-on-chips are trying to shift this perspective and look up from a bigger system, so how can we recreate biological systems in a way that mimics the whole human body?
This chip is engineered to create the right environment for the cells to feel like they are in the human body. So, the first component for an organ-on-a-chip is cells. Our body is full of organs, and you all know each organ is specialized for a different function, and our organs are made up of small functional units, which are made up of different types of cells, well-trained to perform their assigned roles.
Again, we take the example of the heart. Its functional unit is a fiber made from a few heart muscle cells that rhythmically contract. These fibers bundle together to help the heart pump blood throughout the body. Thanks to discoveries in Cell biology and novel technologies, it is now possible to grow the functional units as mini-organs outside the body. We have various cell sources at our disposal, but stem cells are, without a doubt, the most important sources.
Stem cell replication and Organoids
Stem cells are extraordinary cells. They can replicate themselves as often as they want, and we can help them shift into any other cell type of our body at the same time. This process is called differentiation.
A few years ago, scientists found a way to turn skin cells, meaning specialized cells, back into the state of this stemness. Other scientists and groups managed to convince the stem cells to re-specialize even into any other cell type, e.g., heart cells or liver cells. This was a breakthrough discovery for the biomedical sciences.
Organoids are 3D cell structures that contain a multitude of organ-specific cells. We get those miniature organ-like structures by differentiation and self-organization of stem cells isolated from various sources in our own body. Then we treat them with cocktails of very specific molecules and growth factors that direct them towards the specialized cells that we want to study.
Now, organoids and organ chips are not the same things. We use organoids as cell sources that better represent cellular environments in our bodies, and they are better at doing so than the conventional cell cultures in a dish. The ability to self-organize helps organoids mimic general tissue structure and our developmental projection. This can often give us cell types that would have otherwise been difficult to maintain with traditional cell culture methods.
How do cells in an organ-in-a-chip work?
These miniature devices are usually made of polymers. Polymers are huge molecules that contain large chains of many of the same small molecules. Plastic is an example of a polymer. For us, for organ-on-chips, the most common material is PDMS, which is transparent and flexible, unlike plastic. But one could say that the devices on this organ-on-chips look like and are the size of LEGO bricks. As mentioned earlier, these chips contain many channels where the cells grow, and the fluid that nurtures them flows via dedicated ports with the help of specialized pumps. Because these channels and chambers are so small, the polymer breaks are called microfluidic platforms because we can flow liquids and gases through them. This is a term commonly heard when referring to organs-on-chips. The chip comprises multiple layers, the top and bottom layer sandwich a membrane. The microenvironment formed in this chip provides a cozy environment for cells, helping them forget that they are not in the body anymore. It allows cells to arrange themselves in their accustomed figurations and interact with their neighboring cells similar to the way they would in the human body.
(End of Part 1)