Big things to come I think.
Welcome to the antigen-specific revolution.
Welcome to the antigen-specific revolution.
My undergrad mentor got mad at me for being 'too grandiose' in pitching this. Probably isn't grandiose enough tho tbh.
If it's 2019 and you don't know what the hell causes a disease - my guess you've read a paper saying it's due to this boogeyman - inflammation. 
Inflammation is what immunologists say when they see immune cells in a diseased tissue but they actually don't know what the fuck is going on.
Well - guess what. Something is going on. Something VERY SPECIFIC. Something we immunologists like to call 'antigen-specific.'
What the hell does antigen-specific mean? Well that means your immune system recognizing a target (usually a protein) - and seeking it out and destroying (or protecting!) that target. At the molecular level. Mind blowing really.
This process is so sensitive it can recognize and kill a cancer cell with a single-letter amino acid mutation. Crazy. Like for example KRAS G12D is found in ~4% of all cancers - that means we've swapped the 12th amino acid (glycine) for an aspartic acid in that tumor.
In theory (without HLA-specific immunoediting, etc, etc, yes I know please) - you could maybe prevent (ie cure) 4% of cancers with a vaccine to KRAS G12D if it was fully protective.
KRAS G12D and other 'hotspot' mutations in cancer-driving oncogenes are so frequent that in a study of 10,945 cancer patients >38% of all of them shared at least 1 of the top 50.
That means that - maybe - maybe - you could prevent say >1/3 of all cancers - EVERY TYPE OF CANCER - with a fully protective vaccine to these targets:
There's the list. Go order the peptides from pepperprint.com and mix them with some incomplete freund's or poly-I:C, inject yourself, and enjoy the 38% cancer reduction. I mean not really. But maybe? Definitely maybe.
If you want more info it's at the end of my PhD thesis. It's not what I had to write my thesis on - but related enough I got to squeeze it in there. pdfs.semanticscholar.org/6ca0/33e4b4d63…
Ah! Which brings us back to the current topic. ANTIGEN SPECIFICITY. And why it's THE ANSWER to Life, the Universe, and Everything. As it pertains to unsolved mysteries in human health that is.
Here's a pretty picture I made to illustrate this grandiose claim without providing any actual data:
Oh ok you think you've got me. So why do people get cancers - cancers with very specific mutations - when the immune system is able to see changes that are so very very small?
Well that's because as our bodies age - we naturally diverge in a ton of directions. There is in fact no such thing as your genome. That was only true when you were a fertilized egg; essentially all of your adult cells contain mutations of some sort (most harmless).
And so your immune system is constantly worried about harming the mostly-normal tissue - because that's what causes autoimmune disease!
When your immune system is super careful, attacking lots of things that sort of look like you - it can prevent cancer. But it can also cause autoimmune disease.
We actually see this bear out as a difference between the sexes. Men get more cancer. Women get more autoimmune disease. This is because the immune system's thresholds for what it considers 'self' versus 'non-self' are set differently in men and women.
This lack of sensitivity in men allows the body to tolerate more growth and healing (to build muscle, recover from injury), and in women they alter their thresholds during pregnancy to tolerate the fetus. In fact - some chronic autoimmune diseases go away during pregnancy!
BUT IT ISN'T JUST YOUR SEX THAT DETERMINES HOW SENSITIVE YOUR IMMUNE SYSTEM IS. In fact - it's dependent on your entire life history. Literally everything you have encountered.
@larmanlab and colleagues recently demonstrated this memory gets destroyed when you have the measles. science.sciencemag.org/content/366/64…
@larmanlab But normally - it's just there. This background 'fingerprint of stuff' that your immune system sees. And I think it is VERY important to how differential outcomes in human health happen. Even to the point where I think it may determine who will or will not get specific diseases.
A great example of this - that most would incorrectly say is unrelated - is @SBakerMD and his website meatheals.com
Your immune system is very very dependent on your microbiome. Your microbiome is very very dependent on what you eat. Swap what you eat? You swap your microbiome. Swap your microbiome? You swap downstream immune diseases caused by chronic immune reactions to your microbiome.
I believe what the people reporting to @SBakerMD are seeing is that you can relieve chronic immune disease by removing the fiber-loving bacteria that cause these chronic diseases (multiple sclerosis, rheumatoid arthritis, etc.)
But not all chronic conditions will go away by a simple dietary swap. Sometimes the stimuli will still be there on a dramatically different diet, or you'll still need to train the immune system to notice cancer....or avoid harming normal tissues.
And this is how we come back to antigen-specificity. The microbiome may be the upstream cause - but the real place you need to look for what it does is in the immune system. And right now? The best tools we have for that are antibodies.
Tools like HuProt: cdi.bio/huprot/
And HuScan and VirScan: cdi.bio/phip-seq/
Will let us measure what the immune system is doing for the first time at the ANTIGEN-LEVEL.
This has never been done at the level of individual antibody isotypes before. And that's important. Because different isotypes mean very very different things. Like whether the immune system is protecting or destroying things:
I think that ultimately - by surveying people who DON'T GET DISEASES (go read up on survival bias): en.wikipedia.org/wiki/Survivors…
We are going to learn the targets people's immune systems attack that cause dementia. That they don't attack that cause cancer. That they attack to result in healthy aging.
New antibody tools will give us the targets we need to create anti-cancer vaccines, anti-dementia tolerance vaccines, and anti-aging vaccines.
/end thread
