Monday 18 November 2019

The three future dimensions of 3D cultures (organoids)

Imagine going shopping for an organ! I am not referring to the black-market organ trade, but organs that are custom-made for you in a laboratory. The path to creating organs has been laid back by creation of what are called as organoids, which are 3-dimensional cultures of human induced pluripotent stem cells (hiPSC), or simply put mini organs. 

Pluripotency is the ability of a cell to give rise to any of the different body cells like liver cells, heart cells, or neurons and are present only in a developing embryo. Induced pluripotency is when we make normal adult body cells to change into pluripotent cells, thus starting from blood cells we can make first hiPSCs which can form neurons, liver cells and so on. 

Although, it's a far-fetched destination now, but we sure are heading there where it would be possible to replace your faulty livers with a liver made in the lab or a part of liver made from your own body cells.

How are organoids made? It's as simple as taking cells from a person's body, changing it into a type called as human induced pluripotent stem cells (hiPSCs), which can with proper signals be converted to a desired cell type. The next step is much trickier in which these cells are allowed to grow and self-assemble under conditions wherein they form 3D structures resembling mini organs of embryos. Cells are kept with minimal requirements and left on their own to grow for months. Pretty cool, right?

What are organoids used for? Organoids have been in current use for finding the right drugs for an ailment, besides understanding development and developmental disorders. The most interesting among organoids are the brain organoids, which have until recently only been limited to growing just a few regions of brain like the outermost cortex and extensions of brain like retina and sensory organs like the ear and cornea. 

The current technology does not provide a way to integrate these organs together, but it seems possibile in future. Let’s see what are some of the challenges that is preventing that from happening?

1. Creating a blood supply to these organoids.
Organoids don't have vasculature i.e., the organized blood vessel network, and so connecting different parts together and keeping it alive for long is a bit difficult. But aren't there cells that can do exactly that in human body? Yes, I’m talking about cancer cells which are good at creating blood vessels to keep a tumor growing before it starts to metastasize and spread through the blood supply to other tissues. Thus, it would be needed to learn more about how vascularization and angiogenesis happens in tumors, which can then later be modeled into organoids. 3D printing can create blood vessels in an intricate network, creating the scaffold along with matrigel on which iPSCs can be grown, which would require integrating different tissues together. 
The first step has been taken in that direction by researchers at Micromatrix, using vascualture derived from a pig liver by first remiving the cells and then integerating iPSCs into that meshwork of blood vessels. Pretty neat, I would say, eagerly waiting for this work to be pulished soon.

2. Integrating different parts of an organ together.
Self-assembling organoids can be made to work together but that would require 4D cultures. Let me get back to that by first describing the formation of networks in brain organoids which have shown to generate electrical activity like that what is present in embryos. What we need is extraneous cues to guide these networks and let them associate together. That is trickier and much more complex to achieve at this stage, but the vast knowledge of brain circuits and the future advances in techniques like optogenetics, which uses light to switch on and off neurons, can allow for manipulation of specific brain cells makes it less distant than what we might hope. 

3. Ethics of doing the above.
All that said comes the questions of ethics, which has been a matter of debate recently. There are numerous articles that can be read for understanding the fears that brain organoids and their evolution into complete brains are creating among the scientific community and society in general. What  if they become conscious and feel pain? 
Anyone who has watched the British show Black Mirror would be bale to visualize the horrors associated with simulations of a consciousness. It forces us to imagine scenarios that we never have witnessed before along with enetring into a realm of the unknown. I am certain that as the science of organoids would advance so would the need to make rigorous ethical standards and implementing them, which would redefine the existing set of rules and bring new ones into place. So, at the moment there isn't anything to be scared of brain organoids and of a simulated version of you getting stuck for eternity inside a Teddy bear or on a space vessel.




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