Decoding immunity. Autoimmunity is far more common than anyone today expects or understands. CSO @cdi_labs
Oregon
Joined January 2018
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We haven't even begun to collect the training data needed to find the cause and cure of autoimmune-induced chronic disease.
Tyler Hulett retweeted
General prediction of T cell receptor antigen specificity from sequence using AlphaFold 3
science.org/doi/10.1126/scia…
>read about some cool peptide MT-RNR2
>signals outside cells
>common virus proteins look like cool peptide
>know immunity makes antibodies to viruses
>know immunity is fallible
>antibodies also outside of cells
...
>undiscovered autoantibodies blocking peptide probably exist
mfw
>biology is just a data problem
>collect enough omics, simulate the whole cell
>read about humanin
>peptide encoded inside the mitochondrial 16S rRNA gene
>the same sequence is also a structural part of the ribosome
>24 aa if the cytosol translates it, 21 aa if the mitochondria do
>because mitochondria run a different genetic code
>and start translation with N-formylmethionine instead of plain methionine
>nobody's fully sure which one actually makes it
>also 13 nuclear copies that might make their own versions
>gets secreted into the blood
>hits cell-surface receptors
>one of them is literally a mitochondria detector
>also gets taken back up
>binds Bax inside the cell to block apoptosis
>discovered by screening surviving brain tissue from an alzheimer's patient
>open my cell model schema
>compartment: yes
>molecule_type: rRNA, peptide, hormone
>length: depends who's asking
Most of the 'unexplained' chronic diseases are autoimmune conditions with antigens yet-to-be discovered.
Persistent and compartmentalized T cell immunity in ALS @NatureMedicine
nature.com/articles/s41591-0…
And today - half a billion years into vertebrate evolution - we still can't deal with all of cyanobacteria biology.
Learning how to deal with it may help cure ALS & dementia.
And so it would go -->
Swim in Black Lake. Ingest BMAA (or microplastics, paraquat, whatever). It's now in long-lived proteins. Decades 'wait' later, 'tolerance break occurs' (varicella reactivation? autoantibody blocking tolerance?) --> autoimmune attack.
Dementia, ALS, etc.
We can't keep idiots from swapping in a pangolin RBD -- but at least we can stop funding them to serial passage RaTG13 in human cells for the decade beforehand.
I have been reflecting on this for years, and have decided to make the position public. I think there should be an international band on the serial passage of zoonotic (non-human) viruses in human cell lines. Groups may do this for reasons of convenience to adapt the virus to culture more easily in the lab, but the practice risks adapting the virus to human infectivity (anti-attenuation). A non-human cell line (MDCK etc) should be used instead for this purpose. It’s not a perfect defense, but adapting viruses to propagate more easily in human cell lines is an insanely bad example of penny wise and pound foolish lab practice.
Imagine the *majority* of people with psychiatric and mental illness actually have immune-mediated brain disease; they are just very hard to find. Fantastic labs like Chris Bartley's (pictured, not on twitter!) are proving some of those first literal mechanisms.
A subset of people diagnosed with severe psychiatric illnesses may actually have immune-mediated brain diseases. Properly diagnosing and effectively treating these patients is an important area of discovery in the mental health space.
I had a deeply interesting and informative time visiting researchers at the National Institute of Mental Health yesterday, who are working on cutting-edge approaches to that issue and many more.
ALT Dr. Jay Bhattacharya poses in an NIMH lab with a group of scientists and staff.
ALT Dr. Jay Bhattacharya looks on at a screen with a slide reading "Psychosis is a state of disordered information processing". An NIMH researcher explains the slide.
ALT NIH Director Jay Bhattacharya listens to an NIMH employee who is presenting a test tube and wearing purple gloves in a lab.
Last year Chris sent me this very interesting case study he's quoted in where paranoid schizophrenia went away after circulating B cell depletion. Makes you wonder if a BCMA-CAR-T or anti-CD38+ might be even more effective via plasma cell depletion. newyorker.com/magazine/2025/…
A tour de force paper all to show:
One aberrant immune response to one peptide
--> One 'complex' chronic disease
I am ever more convinced most 'complex' chronic diseases are this simple (and impossible to cure without decoding antigen-specific autoimmunity).
Universal seropositivity, markers of recurrent reactivation, and a convergent T-cell response implicate cytomegalovirus in Susac syndrome
researchsquare.com/article/r…
Tyler Hulett retweeted
My daughter has an ultra-rare, autosomal dominant, monogenic neurological disorder with fewer than 200 cases worldwide. It is characterized by haploinsufficiency; however, unlike some genes underlying other genetic diseases, the affected gene is too large to fit into a standard AAV vector for a gene therapy intended to deliver neurons a working copy. I am using GPT-6 Astra and the Rosalind Workbench to design candidate minigenes for my daughter (and others affected) that are sufficiently sized for viral delivery while retaining the most important functional domains of the protein. The idea of minigenes has precedent: Elevidys by Sarepta Therapeutics is FDA approved for Duchenne Muscular Dystrophy and consists of a “micro-dystrophin” transgene about a third of the size of the wild type dystrophin. Specifically within Rosalind I am using the Biological Sequence & Alignment Viewer, Biohub ESM plugin (for folding candidate minigene variants and domains), and the Molecular Structure Viewer (for alignment to the wild-type reference predicted structure). Furthermore, I am leveraging additional databases like ClinVar to cross-reference pathogenic missense variants that suggest regions critical to functional activity, since little is known about the disease in general. I would be exceptionally thankful for the additional credits of the Pro plan as I keep quickly running out of usage, and this is a use case where I most certainly want the best available model.
ALT Minigene variants designed by GPT-6 Astra
Decoding bad antibodies is the way to fix many diseases
Did you know a discovery made during malaria research could someday help people with alpha-gal syndrome?
In this video, I share how NIH researchers identified rare antibodies that may help prevent allergic reactions associated with this tick bite-linked condition. It's a great example of how research can lead to unexpected discoveries with the potential to improve lives.
Learn more: bit.ly/4cnX4Z5
Absolutely love that my projects shut down whenever Astra or Opus notice public UniProt virus sequences in my database.
Taking viral genome sequences off public databases does ~not~ reduce risk of synthetic viral pandemics by >90%
Information hiding will not reduce security risks — the only thing that will actually work is vastly improving our technological capabilities that allow us to produce effective countermeasures with rapid response
Obfuscation is not a meaningful security strategy, as we've learned from decades of cybersecurity practices. It only serves to harm defensive efforts and slow our ability to craft responses
Also see the history of things like Napster and Limewire, pirate bay, Library of Genesis, torrents, etc; Information cannot be prevented from being shared through the world. Attempting to obfuscate it will only harm beneficial defensive efforts