New Technology for Single Cell Analysis in Tissues

I was recently asked about why I spent the past years trying to move the technology forward that I developed at Harvard and MIT. This technology could be of interest to many and I wanted to share my thoughts and hopefully start a new conversation.

Most human organs (except blood) consist of solid tissues, where cells are spatially organized and tightly held together within a scaffold called the extracellular matrix. Cells live in diverse and dynamic communities in solid tissues. Understanding these cell communities at the molecular level is a challenge across the life sciences. For example, the tumor microenvironment currently presents a road block for advancing immunotherapies in solid tumors.

There are three main approaches to study cells in solid tissues: i) tissue disaggregation (disrupting cell communities), ii) tissue fixation (e.g. brains in formalin jars), and iii) optical imaging (microscopes). Almost all relevant methods published over the past century reduce to at least one of these categories. Each category has major technical limitations with respect to measuring molecules in cells.

Our technology provides a radically different approach. Remember how soap can easily remove oil and fat stains? Our technology enables the solubilization process at the scale of single cells in solid tissues. The below videos demonstrate how a high-precision robot operates this technology on a live tissue sample in a semi-automated manner.

Video 1: High-precision robot.
Video 2: Technology applied to two nearby cells in a tissue.

The last video specifically shows how solubilizing/dissociating chemical reagents (bright) are contacted with the intracellular space of a single cell in a solid tissue (dark) and are allowed to spread within the intracellular space of the cell for some time, wherein the cell is solubilized/dissociated from the inside of the cell. The solubilized cell contents are then collected for further analysis and the same process is applied to another cell. The two videos also demonstrate the amenability of this technology to automation. Imagine how it could be improved with more robotics and computer vision!

Why could this technology remain useful in the foreseeable future? When we want to measure something precisely, we need to control the environment. This is difficult or impossible to achieve inside a cell. Therefore, there will always be the need for isolating the biological material from cells in tissues. Our technology for the first time addresses this need by miniaturizing the solubilization process.

The development of this technology was previously funded with a $1M Challenge Grant from the National Institutes of Health. The technology was also described by leading scientists in private conversations as “potentially transformative” and as “radically different from what is available today”.

If you are interested in helping move this technology forward, I hope to speak with you soon 🙂! I am also happy to chat about how computer vision and robotics could further streamline this super cool tech.

Technical notes:

To our knowledge, single cells were never before chemically solubilized in a solid tissue. Detergents were never delivered into the intracellular space of a single cell, as solubilization was never envisioned to be induced from the inside of the cell. The patent applications covering this technology were filed in major international markets.

We already acquired validation data by measuring transcripts and proteins. Measuring metabolites should also be possible. This technology could potentially enable the molecular profiling of cells not only within but also across molecular classes. If you are interested in longitudinal measurements, then it is worth thinking about pulse-chase-type experiments.