The Tech Poised to Disrupt a $30 Billion Market

Labor shortage

In addition to the challenges of the workflow itself, there has been a shortage of histotechnologists for many years now, with current vacancy estimates ranging from 7-10%. Some classify the shortage as a “national crisis”. This shortage doesn’t seem to be improving, and it’s having real effects on pathology turnaround time and throughput capabilities.

Hold on, let’s take a first principles approach and reconsider the entire process

Why are we doing all of this? Not because it’s the best way, but because it’s the way we had to do it with the tools we had at the time. What if those constraints no longer applied?

Let’s step back and think about why we are doing what we are doing now in order to get a pathology image, and then rethink all of this in light of current tech.

With traditional “brightfield microscopy”, the goal is to create a process that allows us to cut tissue thin enough that we can evaluate its features when light is shined through it under a microscope. The image is viewed against a bright (white) background. The light’s interaction with tissue is important here, relying on things such as absorption and reflection to create enough contrast for us to visualize microscopic details. The ideal tissue section ends up being 3-6 micrometers thick. For reference, a red blood cell is only 6-8 microns in diameter. So we are cutting tissue very very thin! If we cut it any thicker, we’d lose the ability to discern microscopic features and eventually we’d get thick enough that visible light wouldn’t pass through.

The problem with cutting tissue this thin, however, is that fresh tissue is just too soft and squishy for us to be able to cut it thin in any reliable way. A good example to illustrate this is: imagine trying to slice a raw and thawed out chicken breast or raw cut of beef very very thin. Maybe you’re trying to cut thin slices to make into jerky. Or, if you’re vegan/vegetarian, imagine trying to cut a freshly baked hot loaf of bread into thin slices right as it comes out of the oven. It’s tough, right? You mangle the tissue up in the process and end up with an ugly slice without uniform thickness. So what do you do to get around the squishiness of the tissue? Well, you freeze the meat (or let the bread cool) and then you cut it while it’s still frozen or semi-frozen in a more solid state, rendering it much more cuttable. This is basically what we’re doing with almost the entirety of the histology workflow. We’re trying to figure out how we get that piece of tissue cut thin enough for brightfield microscopy. To do it, we embed the tissue in a block of wax that is much more firm and cuttable. But we can’t impregnate the tissue with wax and make it rigid when it is still in its normal state because it’s got too much water in it for wax to penetrate. Wax and water don’t mix! So we have to dehydrate the tissues to get the water out and make it possible for wax to impregnate, through a multi-step process we call “tissue processing”. But we also need another important thing to happen even before tissue processing. We need the tissue to be preserved in formalin. This stops the tissue autolysis (decomposition) process that naturally happens as soon as tissue is removed from the body, kills microbes, and stabilizes the tissue, preserving architectural features and rendering it firm and intact for microtome sectioning later on. Without formalin fixation, the tissue would rot before we even started the dehydration and embedding process. Oh yeah, and don’t forget that at the end of all of this, even after we get the ultra-thin slice of tissue we still have to stain it and coverslip it, and then store that slide somewhere.

Because traditional brightfield microscopy is limited by requiring these ultra thin slices of tissue, we have to go to extraordinary lengths to obtain them. And we’ve developed this entire elaborate histology workflow, requiring expensive equipment, trained lab technologists, and a lot of time, just to get to the final product of an image.

There Has to Be a Better Way 

If a new technology could remove 90% of the friction in histopathology, why would we insist on keeping the old workflow intact? While some hybrid applications may persist, the ability to go direct-to-digital changes everything. In this context, it’s a no-brainer. We wouldn’t just pick the slide-free histology-we’d wonder how we ever did it any other way.

Slide-free histology eliminates processing, wax embedding, microtome sectioning, and slide creation. It may also eliminate the dependence on formalin fixation in some applications. This changes the entire histopathology paradigm and allows:

• Imaging fresh tissue directly without hours of fixation
• Rapid pathology reports in hours rather than days
• Affordable and rapid deployment of pathology options for geographically challenging areas.
• Preservation of molecular integrity for downstream testing (DNA/RNA sequencing, proteomics, etc)
• Elimination of processing artifacts caused by chemical fixation and sectioning
• Greater depth visualization and potential for 3D reconstructions
• More robust image analysis AI models

The Future

I hope you see why this is an exciting emerging technology and why there’s opportunity to radically change how we do pathology. But we also have to discuss the challenges ahead including what it will take for the industry to adopt a new workflow. It’s an uphill battle any time a new technology tries to disrupt the norm. Beyond industry inertia, adoption of slide-free histology faces structural, financial, and educational barriers that could slow adoption. Most importantly, we have to evaluate whether it’s diagnostically equivalent to traditional processes or pathologists won’t adopt it. So Next, in Part 2, we’ll dive into the handful of imaging methods being used for slide-free histology and discuss their pros, cons, challenges, and levels of maturity. In Part 3, we’ll cover the companies driving this transformation and who you should be watching.

Disclaimer

I am not currently employed by or affiliated with any company developing slide-free histology technology. However, I previously served as a scientific advisor for Smart Health Dx and hold equity in that company. My opinions in this article are my own and are based on my experience in pathology and my independent analysis of the field. This newsletter is intended for informational purposes only and does not constitute financial, medical, or investment advice.