Making a mouse see-through with wildDISCO

The Problem

Understanding biology is hard.

We use animal models to try and bridge the gap between cell culture experiments and human biology. These models, commonly in rodents like mice or rats, are especially important for understanding new medicines or how diseases progress.

Nothing in your body happens in isolation. Signals and cells travel from one part of the body to another constantly. Some immune cells travel through your blood and invade whatever tissue gets infected by disease, things you eat influence your brain chemistry, you take some ibuprofen for a headache but that also thins out your blood, and so on. Everything connects.

But, we usually only look at a small part of animals during a study. When trying out a new treatment for breast cancer, you look at the tumors. You don’t look across the entire immune system in the whole animal.

Except, that could be useful, right? We use animal models for their complexity, yet it’s impossible to get all the available information out of the model.

There’s been a wave of new techniques designed to solve this problem. These studies focus on improving one of the most used biological characterization tools; imaging.

Their motivation is simple; better imaging gives more information. The more we can image, the more we can learn, and the better we can combat injury and disease.

Imaging tissues requires marking the things you’re interested in, like specific disease markers on a cell, with antibodies that give off a fluorescent signal. This process is called staining. The main problem: antibodies are big and don’t go everywhere they need to.

The Solution

Today’s paper debuts a new technique for antibody staining entire mouse bodies at once. They named it wildDISCO.

Their trick was to remove the cholesterol from tissues as they processed them for antibody staining. Without the cholesterol, tissues become a lot easier for antibodies to enter. They used a modified sugar-like molecule called β-cyclodextrin to do this.

Alright now for the cool part and why I picked this paper. The images.

That’s the artery system of a mouse. The whole thing.

These close-ups show us how neurons interact and spread through other tissues. You can see them in places you’d expect, like the spinal cord (duh) (b), and in places you might be more surprised by, like fat tissue (c). Neurons pretty much go everywhere, including all your major organs (d and e).

After showing off what it can do, the authors used their wildDISCO system to explore some unanswered questions about cancer.

Specifically, many animals/people with cancer develop clusters of immune cells called tertiary lymphoid structures (TLS). These structures are often a good thing and cancer patients with them tend to have better outcomes. But, we don’t understand how TLS interact with tumors and their metastasis.

wildDISCO is perfectly situated to answer that question. With it, the authors could look through the entire body and look for where TLS clusters pop up and why.

They found that TLS clusters tended to form near the primary tumors (in yellow) and near lung and gut metastasis sites. They usually didn’t form near small metastatic sites throughout the rest of the body.

The paper also images the peripheral nervous system, the lymphatic system (analogous to the “blood” system but for your immune system), all the proliferating cells in the body, the microbiome and its effect on nerves, immune cell-nerve interactions, and even more. It’s worth taking a look at!

Whole-body imaging is growing more popular for good reason. It enables scientists to ask questions on a whole-system level instead of looking at one location in isolation. We’ll be seeing it more and more as techniques like wildDISCO make it more accessible to the field.

See you next week for more science,

Neil

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