Trying to raise money for something like that!

I've been working on this area for quite long, and I think it's just a matter of time it becomes huge. Right now, a major roadblock is that single-cell RNA-seq, which may also give paired TCR alpha and beta chain data, is too expensive compared to bulk TCR-seq. The latter has limited resolution and more technical variability.

However, Microsoft Research has a preprint that employs bulk TCR-seq where they are able to detect Lyme, which is particularly difficult to do using antibody assays and often mistaken for multiple sclerosis: https://www.medrxiv.org/content/10.1101/2021.07.30.21261353v...

AFAIK, there are a few startups in stealth mode and non-stealth mode collecting big repertoire datasets. In those datasets, one can even measure the effects of vaccinations that occurred decades ago.

what's the approximate cost difference between scRNA-seq and bulk TCR-seq?

does the cost curve suggest that scRNA-seq costs will reach cost parity with bulk TCR-seq, or become more practical, within X years?

conversely, do you see a way for bulk TCR-seq to overcome issues with resolution and variability?

from the outside, it seems like sequencing is such a fundamental piece of understanding the human body yet technology seems incredibly limiting.

it's amazing what scientists have discovered so far. imagine what happens if we can help people observe cells more affordably and more accurately.

Bulk TCR sequencing cost around $500 to $1000 and captures under a million T cells. scRNA Seq costs around $10,000 and captures under ten thousand T cells. The price of sequencing is falling exponentially so my numbers can be out of date

These figures are approximately right. We've been able to bring the cost of single-cell RNA-seq + TCR-seq runs down to $3000 by doing targeted gene expression, which requires less reads. Besides, some newer microfluidics platforms are able to yield more cells, close to 2e4.

I would say that the major limiting factor is the microfluidics platform. Ideally, we would require something that has a yield within the same order of magnitude of bulk methods. To address this limitation, one can e.g. pre-sort activated cells. Otherwise, the number of receptors is typically not enough to be able to observe meaningful statistical patterns.

Parse biosciences and companies have developed methods to perform TCR sequencing without the microfluidics and it will be interesting to see how well it performs. These methods are all based on permeabilizing the cell and keeping it intact instead of encapsulating the in a droplet and then lysing it.

Microsoft Research was a partner in the joint collaboration. Pretty sure this was the research that culminated in the T-Detect Lyme product that Adaptive Biotech launched last year (definitely some Adaptive representation in the publication).

https://investors.adaptivebiotech.com/news-releases/news-rel...

I wonder if low-hanging fruit is just "immune system health". train on healthy vs unhealthy immune systems and give a status bar.

I've read that healthy individuals don't get cancer because their body nips it in the bud. Why couldn't we just figure out if people are pre-cancer (susceptible), like pre-diabetes?

Age is probably the biggest influence on a "healthy" immune system. I haven't kept up with recent research, but if memory serves the immune repertoire (diversity of T and B cell receptors) decreases essentially linearly with age.

Here's some supporting research from a quick search. https://journals.aai.org/jimmunol/article/192/6/2689/1552

Edit: some fun but possibly pontificating tangents

This seems to be part of the reason why vaccines have had relatively poorer efficacy in elderly populations. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3901832/ https://www.nature.com/articles/s41586-021-03739-1

I'm hopeful that cancer and immune profiling will be able to be used in tandem to (1) identify cancer early and (2) identify gaps in the immune repertoire to facilitate (3) design of antibodies that specifically target the cancer.

There's a huge variability in the age of thymic involution. Some people have a relatively active thymus at age 50 or 60, whereas in others it has switched off by age 25 or 30.

For those not familiar with immunology, the thymus is what populates your immune system with brand new T cells with freshly selected T cell receptors.

This suggests interesting anti-ageing opportunities, such as artificial thymi to repopulate your immune system and keep a healthy and diverse repertoire.

I wasn't aware of the variability in thymic involution. I guess most studies focus on averages. If you have links to more information about these outliers I'd be very interested in reading up on them.

The most recent literature that I'm seeing is showing the most pronounced time of thymus involution occurring around puberty, suggesting a programmed switch from a growing to reproductive phase of life.

"Regardless of the seemingly crucial role of the thymus in preserving homeostasis, its involution in humans and other mammals begins in childhood and peaks around puberty, resulting in an almost completely non-functional organ in aging." https://www.sciencedirect.com/science/article/pii/S156816372...

In this light the following makes sense (stopping or suppressing the switch to a reproductive life). "Castrating rodents before puberty or reducing the levels of sex hormones [e.g., by using Lupron, which desensitizes the luteinizing hormone-releasing hormone (LHRH) receptors] can attenuate or markedly recover the involution process in aging mice."

This study presents a gene expression marker for recent thymic emigrants and shows variability increases with age: https://insight.jci.org/articles/view/93739/figure/5

A much older study with different markers shows something similar: https://www.pnas.org/doi/epdf/10.1073/pnas.070061597

unrelated but spurred by this comment, have you seen studies exploring correlations between covid infection/severity and tonsils? a cursory google search yielded nothing.

See BRCA1 mutation

May I ask, what are your qualifications and how did you get a job in this field?

I'm surprised as well. I thought the problem with cancer is that the immune system doesn't react/detect it and therefore might not provide a discernible signal.

Sure, that's the problem with cancer. But to get there first, your immune repertoire has become less diverse and developed some holes due to infections, dysbiosis, aging, etc.

There's usually going to be some signal though even if it was just localized downregulation of some proteins on immune cells induced by a cancer to escape detection. The trouble there is that may be swamped in a systemic serum sample. Looking at subsets are more useful to improve signal to noise ratio like looking at extracellular vesicles released by tumour and immune cells for messaging purposes