Co-Founder @ Xaira Therapeutics Former Baker Lab PostDoc at @UWproteindesign. Interested in generative modelling for molecular design. Views my own.
Joined September 2020
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Joseph Watson retweeted
We’ve been quiet about protein design at @Xaira_Thera . Here’s what we’ve been building:
Introducing X-Design, with results from two active drug programs that show what we think this field needs to deliver: speed to a useful lead, and access to targets that have resisted discovery.
→ 7 weeks from DNA synthesis to a preclinical lead on an oncology target, with the epitope and reagents already prepared.
→ A functional antibody antagonist against a challenging GPCR where conventional library screening AND llama immunization had failed.
The bar we set for our model goes well beyond binding.
The antibodies need to be human-like, functional, cross-reactive across species, and developable. Properties that have to come together in the same molecule for a program to move forward.
That’s what makes these results exciting to me: designs tested in the lab, meeting the requirements of real programs in our pipeline.
My bet is that the biggest impact of AI protein design will be expanding which diseases and targets we can pursue.
We want to choose targets because the biology is compelling and to build the ability to make the right molecules.
This is our first look at X-Design. Much more to come.
See our blog: xaira.com/news/de-novo-desig…
When we started @Xaira_Thera we were clear that for molecular AI to make a difference for patients, it had to be able to address the hardest and most clinically relevant problems; those that traditional methods haven't been able to solve.
For that, we've been building X-Design, bringing together top-tier research, engineering and wet lab capabilities into a model focused on designing clinically progressible molecules.
Today, we showcase just some of that work; designing functional, progressible antibodies for our "undruggable" XA-4 program de novo.
bit.ly/4hAOhEW
Finally, for the past year or so, some of us have been working to build the next generation of these tools at Xaira Therapeutics (@Xaira_Thera), with the aim of fully realising the promise of therapeutics design. If you’re interested in being a part of it, do get in touch!
In particular, thank you to the other lead authors, @naterbennett0, @RobertRagotte, @AndrewJBorst, @dejsee, Connor Weidle, @wanderingriti and Yutong Yu! And thanks as always to David Baker for the leadership and for creating such a vibrant and exciting scientific environment!
Altogether, we believe this work is a major step towards routine therapeutic antibody design. This was an amazing collaboration with so many passionate and bright scientists at @UWproteindesign and beyond. Thanks to all the authors!
The second is a challenging peptide-MHC complex with clinical relevance. We demonstrate that RFdiffusion can design scFvs that bind. What’s more, mutating a single amino acid on the target peptide totally abolished binding, highlighting the specificity possible with RFdiffusion.
The first has no known VHH or antibody binder to it in the training set. Two structures (one high resolution) demonstrate structural accuracy of the designs.
For many clinical applications, two-Fv antibodies are preferred (as these are the human antibody format). We therefore combined our structure-based design method and novel experimental techniques to design scFv binders to two targets.
A year ago, we posted a preprint demonstrating that a fine-tuned RFdiffusion network could design de novo VHHs (nanobodies). We’ve extended that work, and demonstrate the structurally accurate design of a VHH to an epitope without such a binder in the PDB (i.e., the training set)
We are also releasing inference code for the whole pipeline, free and fully open source!
github.com/RosettaCommons/RF…
This is work performed at @UWproteindesign in collaboration with a plethora of amazing scientists!
I’m excited to share our significantly-updated preprint on de novo antibody design, where we now demonstrate the structurally accurate design of scFvs (in addition to VHHs) with RFdiffusion! biorxiv.org/content/10.1101/…
All the big things happening to all the best Davids!
Congratulations David 😍
⚛️ I got a new job ⚛️
After 5 wonderful years at @UWproteindesign and @UWMolES, I’m headed to Palo Alto for a postdoc at @StanfordUChem under Todd Martinez.
SUPER excited to dive into deep learning for quantum chemistry and explore the Bay Area!!
Congratulations to all - incredibly deserved! It was a total and constant honour working with David. His passion for protein design and its applications, as well as his uncanny attention to detail continue to inspire me. And nothing we do today would be possible without AlphaFold
BREAKING NEWS
The Royal Swedish Academy of Sciences has decided to award the 2024 #NobelPrize in Chemistry with one half to David Baker “for computational protein design” and the other half jointly to Demis Hassabis and John M. Jumper “for protein structure prediction.”
Very exciting to see this work out! It still feels quite amazing that you can take three functional bits of protein and bring them all together with novel scaffolds, all while retaining their native function. Congratulations to @karla_mcastro for leading this super cool project!
protein design is getting weird ... and increasingly functional ! These are very weird designs !
biorxiv.org/content/10.1101/…
fun collaboration with @karla_mcastro @_JosephWatson @jueseph @UWproteindesign
A great day for science!
Congratulations to the teams at @GoogleDeepMind @IsomorphicLabs!!
Announcing AlphaFold 3: our state-of-the-art AI model for predicting the structure and interactions of all life’s molecules. 🧬
Here’s how we built it with @IsomorphicLabs and what it means for biology. 🧵 dpmd.ai/3URDiNo
Joseph Watson retweeted
I am pleased to share that I have accepted a position @Stanford to start as an assistant professor in the department of statistics, with an affiliation in @StanfordData, this fall!
I 100% agree! The sleeper is so great, and incredibly convenient, but since the upgrade it's just way too expensive to get a bed. Shared rooms would still be much more comfortable than the seats!
We're extremely grateful and excited to have the backing to try and realise this vision! I'm very excited to work with our growing team of amazing people in the UK and US.
Read more about the project here:
endpts.com/in-biggest-ever-b…
