Biotech Notes #1: OpenCRISPR, The Halo, Boosted Breeding
Biotech Notes #1: OpenCRISPR, The Halo, Boosted Breeding
OpenCRISPR, by Profluent
Just like ChatGPT predicts one word after the other, the company Profluent has developed an LLM model that predicts amino acid sequences… like new Cas enzymes of all types, including base editors, that they’re open-sourcing, which may just free innovation in the field from the long-debated patent on CRISPR.
In their paper, they share how they produced 4 million sequences with comparable or improved activity and specificity relative to Cas9 that are at least 400 mutations away in sequence from any previous enzymes. Half of these were generated from the model, half guided from a natural protein towards a particular CRISPR family using <50 N or C-terminal residues as prompts.
The model was pre-trained on non-CRISPR proteins across the evolutionary tree (unsupervised pre-training) then by using more than 1 million CRISPR-Cas operons of different types found in microbial genomes and metagenomes (fine-tuning).
Some other technical details I found interesting: in total, only 48.2% of generated proteins were functionally complete (had core Cas9 domains), and the generated proteins were predicted by AlphaFold2 (pLDDT > 80 for 81% of structures) which feels a lot like making two AIs hold a biological conversation.
As a company, Profluent is a spin-out of a Salesforce-funded project to develop an LLM for amino acids called ProGen. Their Chief of Business, Hilary Eaton, has shared their plans to research institutions and drug developers to safely expedite the development of new CRISPR genetic therapies. For now, their CRISPR enzymes (not the model!) will be available for use free of cost under a term sheet that restricts use in germline cells and non-reproducing plants.
Though I understand this at an extremely superficial level, I’m still wondering, on the bio IP side, what the limits or guidelines are and how generative AI will redefine them. Is there a percentage or number of amino acids or bases that mark the limit between infringing a patent and not?
The Halo, by Prophetic
When hearing the words “Brain-Computer Interface (BCI)”, my mind immediately goes to Neuralink with a clear patient in mind, consumer devices like Muse and recently Apple’s patent on new Airpods that could have them but that’s topic for another time. Today’s topic is: what if instead of just recording, you stimulated your brain to have new experiences?
Prophetic is building technology to stabilize and induce lucid dreaming, which is the somewhat weird state in which you’re actively dreaming and become aware that you’re asleep. Free from conventional laws of physics, lucid dreaming cannot only be an interesting and fun experience (you can fly!) but also perfect for problem solving and, in the eyes of Prophetic’s visionary founder Eric Wollberg, a new way to explore consciousness.
The Halo is a non-invasive and wearable device that integrates EEG and focused ultrasound. The EEG detects when the user is in REM sleep and feeds that data into a transformer model to know what ultrasonic pulses to applied and when, in order to mimic the naturally occurring neural activation patterns known to generate lucid dreaming. ChatGPT tech applied to dreams, i.e. WAY COOLER.
A tech that’s used while you sleep and that deals with the brain doesn’t sound like an easy regulatory and safety deal. Though others have found focused ultrasound to be safe for medical applications, the Prophetic uses values below the FDA’s regulations for diagnostic ultrasound and is developing fail-safe mechanisms to ensure these values cannot be exceeded under any circumstance.
The founders have attracted great talent like Sterling Crispin who worked at Apple for 3 years on the VisionPro team as a Neurotechnology Prototyping Researcher, Afshin Mehin and team who designed the Neuralink N1, and Dr. Martin Dresler from the Donders Centre for Cognitive Neuroimaging at Radboud University in the Netherlands.
Before his death, Steve Jobs said that the next generation of great companies would be at the intersection of biology and technology. Apple not only created new products but entirely new markets and though it’s still quite early, I think this is what Prophetic might do when the world is ready for a new market of extra-human experiences.
Boosted Breeding, by Ohalo
In the most recent All-In podcast episode, David Friedberg shared what his company, Ohalo Genetics, has been developing for the past 5 years in stealth mode. Their Boosted Breeding tech is already multiplying the yield of crops significantly. They’ve grown the same potatoes we know, but instead of getting 9 or 100 g, they got 682 g.
Though he didn’t mention it on the pod, it’s clear from their patent that Boosted Breeding uses gene editing tools like CRISPR to knock out 3 meiosis genes in plants so instead of splitting the genes from each parent, they inherit all the genes from both parents.
Having more genetic material allows plants to form more complex gene networks that help them protect themselves against environmental stresses and grow more food, and it makes it easier for farmers to cultivate the crops because all the seeds they get from the plants are genetically identical. Just for potato, they’re changing its millenary reproduction altogether by developing a seed instead of having to use the actual potatoes for their tubers.
Some questions that I’m yet to answer, out of ignorance of biology principles are: does this mean that every time I cross these polyploid non-meiotic plants, I will double the sets of genes they have? What are the limits for polyploidy in each plant then? How exactly does polyploidy help the plants produce more potatoes? How much does this decrease the need for fertilizer, if at all?
Brain bioremediation, by ???
I’m very rarely shocked by pessimistic information and learning about the potential affectations to our nervous system (increased risk of diseases like Alzheimers), cancer genetics (epigenetic disruption), and reproductive health last weekend almost made me cry out of fear of what may be happening to my body and I cannot control, except maybe by moving to a less polluted city.
Right now these studies are mostly statistical correlations and we don’t know the long-term consequences that younger generations like mine will have to face due to breathing increasingly polluted air longer than any generation ever has. We need more rigorous studies on the mechanisms by which air particles interact with our various body systems at different organizational levels and we need to know what other consequences they may be causing right now that we are unaware of.
To prevent this post from ending on a pessimistic note, I would love for my friend Shelby’s thesis on in-vivo detoxification/bioremediation to be expanded to clean ourselves from particulate matter. Until we learn more about the role of these toxic agents in our health, godspeed enzyme engineering to capture carbon directly from the air and turn it into useful products!
Hey, Sofia here — Biotech Notes is a new format I’m trying out to teach myself about things I’ve been curious about but don’t have enough time to write a whole article on. I don’t know how often I’ll be able to ship these but I do know that I will also be sharing these in Spanish under a new Substack tab to evangelize our awesome biotech future to more awesome people around the world. Thanks for following the journey! :)