Tissue Transparency Technology – CLARITY: A Revolutionary Leap Forward in Brain Research?

Tissue transparency technology CLARITY is an innovative way to make brain tissue transparent using hydrogels to enable high-resolution three-dimensional imaging. This could be utilized not only for brain research, but also for a variety of other diseases, but processing speed and cost need to be addressed.

 

The human brain is one of the most complex organs in the body. The number of neurons (the basic unit cells of the nervous system) in the brain is about 100 billion, which is similar to the number of stars in our galaxy, the Milky Way, of which our solar system is a part. The human brain is so intricately connected with such a large number of cells that its structure and function are not fully understood. In order to understand this complex biological system, we need to understand the characteristics and functions of the cells that make up the brain, as well as their arrangement and connections, which requires a high-resolution three-dimensional map, a blueprint of the human body with cellular-level resolution. Tissue transparency is a breakthrough technology for creating such high-resolution 3D maps.
Before we dive into what organizational transparency is, let’s take a look at how it came to be. Scientists have been trying to create high-resolution maps of the human body for organizational studies. Traditionally, tissues such as the brain have been imaged using methods such as computed tomography (CT), magnetic resonance imaging (MRI), or optical coherent tomography (OCT). These methods have been effective for studying structure and function because they allow for three-dimensional representation of living human tissue. However, the resolution is not high enough to show individual cell features or connections, and it is difficult to obtain molecular-level information. This is because the high density of cells creates a kind of barrier that prevents light and chemicals from entering the tissue. Therefore, high-resolution microscopy, which can see down to the smallest cells in living tissue, is currently considered the most advanced method for creating three-dimensional maps. However, when looking at large, opaque tissues such as the brain, high-resolution microscopy is limited by the need to image very thin slices of tissue. Thousands of two-dimensional images have to be recombined and stitched together into a three-dimensional map, which reduces the overall efficiency. Much research has been done to solve this problem, and recently, tissue transparency techniques have been developed.
Tissue transparency technology is a technology that makes opaque tissues of organs transparent with special chemicals and has opened the way to overcome the limitations of high-resolution microscopy. The recently developed CLARITY technology enables observations with about 2,000 times the resolution of magnetic resonance imaging. CLARITY technology synthesizes a transparent, porous polymer net called a “hydrogel” within the tissue, preserving the tissue structure and molecules in three dimensions while completely removing the lipids that make the tissue opaque. In addition to making the tissue highly transparent, it also completely removes barriers that prevent light and molecular probes from penetrating, allowing light and molecular probes to easily penetrate the tissue. The key to CLARITY is that despite the complete removal of barriers such as cell walls, the hydrogel preserves the three-dimensional information of the tissue at the molecular level, so that the detailed morphology of the cells and the connections between them are well preserved. As a result, CLARITY-treated tissues become optically transparent, allowing light to penetrate deeply, and even thick tissues such as the brain can be imaged directly under a high-resolution microscope without sectioning. Another advantage of CLARITY technology is the ability to image the three-dimensional distribution of specific molecules by staining the molecules in the tissue with organic dyes that are covalently linked to the hydrogel. The organic dyes can be removed without destroying the tissue structure or molecules, allowing for repeated analysis of different molecular phenotypes. Furthermore, CLARITY technology can render most organs transparent, allowing for three-dimensional imaging, which can be used not only in brain science but also to study disease in organs through biopsy.
It’s not all rosy for CLARITY, however. There are still a few challenges that need to be addressed. The first is speeding up the process. Unlike analyzing thin sections, it takes months to process large samples like mouse brains. This is because the process of delivering chemicals deep into the tissue to preserve, clarify, and stain it is very slow. Subsequent research is being conducted to address this, with the Active Clarity Technique (ACT), which is up to 30 times faster than CLARITY, being developed in Korea. The second challenge is to reduce costs. The larger the size of the tissue to be analyzed, the more compounds are needed to make it transparent, as well as the amount of organic dyes, which are key to obtaining molecular information. Overcoming these low speed and high cost limitations will be key to commercializing 3D mapping technology.
In this article, we have discussed the background of organizational transparency technology development, CLARITY technology, and challenges. How will these CLARITY technologies impact humanity? Since Watson and Crick discovered the double helix structure of DNA, the Human Genome Project has sequenced genes to complete the human genetic map. Furthermore, CLARITY technology will contribute to the completion of a high-resolution map of the human body, which will answer the question of how the cells in which genes are expressed are connected to each other. In the near future, the structure and function of the brain’s nerve cells will be revealed, leading to treatments for intractable brain diseases such as Alzheimer’s and Parkinson’s.