10 ms·

Diagnosing cancer by profiling the immune system

219 points by jostmey 4y ago

ajb 4y ago
Getting a readout of the immune system sounds like a huge advance. I'm a little surprised to first hear about it as a cancer diagnosis tool rather than as an autoimmune disease diagnosis tool
- jostmey 4y ago
  Trying to raise money for something like that! We have exciting preliminary results
- nextos 4y ago
  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/10.1101/2021.07.30.21261353v2 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.
  - panabee 4y 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.
    - jostmey 4y ago
      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 The price of sequencing is falling exponentially so my numbers can be out of date
      - nextos 4y ago
        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.
        gww 4y ago
        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.
  - genomer 4y ago
    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-release-details/adaptive-biotechnologies-launches-t-detecttm-lyme-new-t-cell https://investors.adaptivebiotech.com/news-releases/news-rel...
  - m463 4y ago
    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?
    - genomer 4y ago
      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 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.ncbi.nlm.nih.gov/pmc/articles/PMC3901832/ https://www.nature.com/articles/s41586-021-03739-1 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.
      - nextos 4y ago
        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 equipped with freshly selected T cell receptors. This suggests interesting anti-aging opportunities, such as artificial thymi to repopulate your immune system and keep a healthy and diverse repertoire.
        panabee 4y ago
        unrelated but spurred by this comment, have you seen studies exploring correlations between covid infection/severity and tonsils? a cursory google search yielded nothing.
  - jeffybefffy519 4y ago
    May I ask, what are your qualifications and how did you get a job in this field?
- genomer 4y ago
  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.
  - nextos 4y ago
    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.
  - kuhewa 4y ago
    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
jjtheblunt 4y ago
This was a plot twist in an episode of CSI:Miami several years ago. Identical twins were implicated in a crime for which DNA was left behind, and they thought they were safe by being twins. But they also had distinct T cell (etc) signatures and that solved the case.
- thfuran 4y ago
  Due to mutations, identical twins probably don't even have identical DNA by the time they're born, let alone in their adult life. I don't think forensic DNA testing is a full sequencing though.
  - jostmey 4y ago
    It is even more complicated than that! Some immune cells, like T cells, will actually edit their own DNA through a process named V(D)J recombination. So the immune system is actually editing some of its own DNA! https://en.wikipedia.org/wiki/V(D)J_recombination https://en.wikipedia.org/wiki/V(D)J_recombination
    - jjtheblunt 4y ago
      Like Lisp reader programming for dsl creation?
    - thfuran 4y ago
      Right, but I mean even of non immune cells.
- robocat 4y ago
  Human Chimeras[1] are even more weirder: one person with cells from two fraternal twins. Causes real problems with maternal[2] and paternal[3] DNA testing. Even more problems[4] if the twins are male and female. [1] https://duckduckgo.com/?q=human+chimera https://duckduckgo.com/?q=human+chimera [2] https://wikipedia.org/wiki/Lydia_Fairchild https://wikipedia.org/wiki/Lydia_Fairchild — Fairchild stood accused of fraud by either claiming benefits for other people's children, or taking part in a surrogacy scam, and records of her prior births were put similarly in doubt . . . [3] https://time.com/4091210/chimera-twins/ https://time.com/4091210/chimera-twins/ — the father had absorbed some of his twin's cells when he was a fetus, effectively becoming a chimera of himself and his brother. The man's previous child's DNA matched his . . . [4] https://wikipedia.org/wiki/46,XX/46,XY https://wikipedia.org/wiki/46,XX/46,XY Sex-chromosome discordant chimerism (XX/XY chimerism)
penny11k 4y ago
Regarding cancer treatment, wonder how much more advancement did they get on that polio treatment. Where lot of test subjects with a brain tumor was treated by injecting polio virus into them. https://www.uhhospitals.org/blog/articles/2020/01/clinical-trial-studies-treating-brain-tumor-with-genetically-modified-poliovirus https://www.uhhospitals.org/blog/articles/2020/01/clinical-t...
rosywoozlechan 4y ago
All the really interesting stuff is always written in python, (AI, science research stuff like this). Here I am and I haven't written any python in over 10 years now, ever since go overtook python after it's v3 debacle.
- jkingsman 4y ago
  > go overtook python > All the really interesting stuff is always written in python Those might not be super compatible statements ¯\_(ツ)_/¯
  - m463 4y ago
    It could be in the venn diagram, "stuff rosywoozlechan has written in the past 10 years" and "really interesting stuff" do not intersect.
- voz_ 4y ago
  [flagged]
moneywoes 4y ago
As someone with a lot of auto immune diseases how do I get tested
marymkearney 4y ago
This is really cool. Thanks for sharing. It validates the perspective of the late great Pieter Hintjens on this topic. https://github.com/hintjens/confessions/blob/master/ch08.txt https://github.com/hintjens/confessions/blob/master/ch08.txt "In my body right now there is a holy war going on, and has been raging for years. My immune system has been doing its damned best to kill these rogue cells. And the rogue cells, unaware that they're destroying their own host, have been fighting back. "The odds are on the cancer, of course, which is why this family of diseases is a major killer. Our bodies have to keep winning, year after year. Any given cancer has to win only once, and it's Game Over. The only way to beat cancer, really, is to die from something else first. "Everyone fights cancer, all our lives long. From birth, our immune systems are hunting down and killing rogue cells.... We are all cancer survivors, until we're not. "
- jvanderbot 4y ago
  I discovered ZMQ after his death. Reading his last posts were perspective-shifting. I genuinely felt sad, both for him as an individual, and because many of his best works are not going to survive much longer than he did. Life is short and our impacts are transient.
  - marymkearney 4y ago
    I learned a lot from his writing. This view of the immune system really shifted my perceptions too. Maybe having your work help people, even years after your death, isn't a bad legacy.
    - jostmey 4y ago
      I just skimmed his text, and it is apparent that he thought deeply about cancer, death, and living. I don't think technology will eliminate all cancer, but from data I've seen, I'm convinced that cancer immunotherapy will help us control many cancers, and the technology is just getting started
    - chaostheory 4y ago
      He’s gained immortality through his work.
adamredwoods 4y ago
I don't understand what Atchley factors are, here's the paper: https://www.pnas.org/doi/full/10.1073/pnas.0408677102 https://www.pnas.org/doi/full/10.1073/pnas.0408677102
jostmey 4y ago
Author here. We’re bringing this technology to market. We’ve identified specific use cases where these methods can impact clinical decision making. Here’s our LinkedIn page: https://www.linkedin.com/company/immunoscope https://www.linkedin.com/company/immunoscope . We’re looking to do our first raise
- ugh123 4y ago
  What studies, experiments, and/or trials has this gone through? Also, I see a list of "Publications" linked, but unsure how they relate to the work done here. "Diagnosing cancer by profiling the immune system" is a bold statement to make while merely linking to a github repo. The readme still leaves A LOT of questions
  - arthur2e5 4y ago
    The publications all appear to do what the README is describing, except for the part where the README says bugs are preventing some results from being reproduced. Going through the stuff chronologically seems to help understand how the ideas got put together. The 2017 MS paper is the oldest of the four and mentions a weaker MSPrecise method using summary statistics. I mean… if we really are sure some two things are somehow related, you might as well throw ML at it and see what it comes up. It's just linear, no super fancy models.
Aardwolf 4y ago
How do you get your data into this software though? What devices do you need for that?

219 points by jostmey 4y ago

ajb 4y ago

Getting a readout of the immune system sounds like a huge advance. I'm a little surprised to first hear about it as a cancer diagnosis tool rather than as an autoimmune disease diagnosis tool

jostmey 4y ago
Trying to raise money for something like that! We have exciting preliminary results
nextos 4y ago
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/10.1101/2021.07.30.21261353v2 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.
- panabee 4y 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.
  - jostmey 4y ago
    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
    - nextos 4y ago
      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.
      - gww 4y ago
        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.
- genomer 4y ago
  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-release-details/adaptive-biotechnologies-launches-t-detecttm-lyme-new-t-cell https://investors.adaptivebiotech.com/news-releases/news-rel...
- m463 4y ago
  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?
  - genomer 4y ago
    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 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.ncbi.nlm.nih.gov/pmc/articles/PMC3901832/ https://www.nature.com/articles/s41586-021-03739-1 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.
    - nextos 4y ago
      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 equipped with freshly selected T cell receptors. This suggests interesting anti-aging opportunities, such as artificial thymi to repopulate your immune system and keep a healthy and diverse repertoire.
      - panabee 4y ago
        unrelated but spurred by this comment, have you seen studies exploring correlations between covid infection/severity and tonsils? a cursory google search yielded nothing.
- jeffybefffy519 4y ago
  May I ask, what are your qualifications and how did you get a job in this field?
genomer 4y ago
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.
- nextos 4y ago
  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.
- kuhewa 4y ago
  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

jjtheblunt 4y ago

This was a plot twist in an episode of CSI:Miami several years ago. Identical twins were implicated in a crime for which DNA was left behind, and they thought they were safe by being twins. But they also had distinct T cell (etc) signatures and that solved the case.

thfuran 4y ago
Due to mutations, identical twins probably don't even have identical DNA by the time they're born, let alone in their adult life. I don't think forensic DNA testing is a full sequencing though.
- jostmey 4y ago
  It is even more complicated than that! Some immune cells, like T cells, will actually edit their own DNA through a process named V(D)J recombination. So the immune system is actually editing some of its own DNA! https://en.wikipedia.org/wiki/V(D)J_recombination https://en.wikipedia.org/wiki/V(D)J_recombination
  - jjtheblunt 4y ago
    Like Lisp reader programming for dsl creation?
  - thfuran 4y ago
    Right, but I mean even of non immune cells.
robocat 4y ago
Human Chimeras[1] are even more weirder: one person with cells from two fraternal twins. Causes real problems with maternal[2] and paternal[3] DNA testing. Even more problems[4] if the twins are male and female. [1] https://duckduckgo.com/?q=human+chimera https://duckduckgo.com/?q=human+chimera [2] https://wikipedia.org/wiki/Lydia_Fairchild https://wikipedia.org/wiki/Lydia_Fairchild — Fairchild stood accused of fraud by either claiming benefits for other people's children, or taking part in a surrogacy scam, and records of her prior births were put similarly in doubt . . . [3] https://time.com/4091210/chimera-twins/ https://time.com/4091210/chimera-twins/ — the father had absorbed some of his twin's cells when he was a fetus, effectively becoming a chimera of himself and his brother. The man's previous child's DNA matched his . . . [4] https://wikipedia.org/wiki/46,XX/46,XY https://wikipedia.org/wiki/46,XX/46,XY Sex-chromosome discordant chimerism (XX/XY chimerism)

penny11k 4y ago

Regarding cancer treatment, wonder how much more advancement did they get on that polio treatment. Where lot of test subjects with a brain tumor was treated by injecting polio virus into them. https://www.uhhospitals.org/blog/articles/2020/01/clinical-trial-studies-treating-brain-tumor-with-genetically-modified-poliovirus https://www.uhhospitals.org/blog/articles/2020/01/clinical-t...

rosywoozlechan 4y ago

All the really interesting stuff is always written in python, (AI, science research stuff like this). Here I am and I haven't written any python in over 10 years now, ever since go overtook python after it's v3 debacle.

jkingsman 4y ago
> go overtook python > All the really interesting stuff is always written in python Those might not be super compatible statements ¯\_(ツ)_/¯
- m463 4y ago
  It could be in the venn diagram, "stuff rosywoozlechan has written in the past 10 years" and "really interesting stuff" do not intersect.
voz_ 4y ago
[flagged]

moneywoes 4y ago

As someone with a lot of auto immune diseases how do I get tested

marymkearney 4y ago

This is really cool. Thanks for sharing. It validates the perspective of the late great Pieter Hintjens on this topic. https://github.com/hintjens/confessions/blob/master/ch08.txt https://github.com/hintjens/confessions/blob/master/ch08.txt "In my body right now there is a holy war going on, and has been raging for years. My immune system has been doing its damned best to kill these rogue cells. And the rogue cells, unaware that they're destroying their own host, have been fighting back. "The odds are on the cancer, of course, which is why this family of diseases is a major killer. Our bodies have to keep winning, year after year. Any given cancer has to win only once, and it's Game Over. The only way to beat cancer, really, is to die from something else first. "Everyone fights cancer, all our lives long. From birth, our immune systems are hunting down and killing rogue cells.... We are all cancer survivors, until we're not. "

jvanderbot 4y ago
I discovered ZMQ after his death. Reading his last posts were perspective-shifting. I genuinely felt sad, both for him as an individual, and because many of his best works are not going to survive much longer than he did. Life is short and our impacts are transient.
- marymkearney 4y ago
  I learned a lot from his writing. This view of the immune system really shifted my perceptions too. Maybe having your work help people, even years after your death, isn't a bad legacy.
  - jostmey 4y ago
    I just skimmed his text, and it is apparent that he thought deeply about cancer, death, and living. I don't think technology will eliminate all cancer, but from data I've seen, I'm convinced that cancer immunotherapy will help us control many cancers, and the technology is just getting started
  - chaostheory 4y ago
    He’s gained immortality through his work.

adamredwoods 4y ago

I don't understand what Atchley factors are, here's the paper: https://www.pnas.org/doi/full/10.1073/pnas.0408677102 https://www.pnas.org/doi/full/10.1073/pnas.0408677102

jostmey 4y ago

Author here. We’re bringing this technology to market. We’ve identified specific use cases where these methods can impact clinical decision making. Here’s our LinkedIn page: https://www.linkedin.com/company/immunoscope https://www.linkedin.com/company/immunoscope . We’re looking to do our first raise

ugh123 4y ago
What studies, experiments, and/or trials has this gone through? Also, I see a list of "Publications" linked, but unsure how they relate to the work done here. "Diagnosing cancer by profiling the immune system" is a bold statement to make while merely linking to a github repo. The readme still leaves A LOT of questions
- arthur2e5 4y ago
  The publications all appear to do what the README is describing, except for the part where the README says bugs are preventing some results from being reproduced. Going through the stuff chronologically seems to help understand how the ideas got put together. The 2017 MS paper is the oldest of the four and mentions a weaker MSPrecise method using summary statistics. I mean… if we really are sure some two things are somehow related, you might as well throw ML at it and see what it comes up. It's just linear, no super fancy models.

Aardwolf 4y ago

How do you get your data into this software though? What devices do you need for that?