Ben Lehner

TF-MAPS: fast high-resolution functional and allosteric mapping of DNA-binding proteins Transcription factors (TFs) bind specific DNA sequences to control gene expression. Modulating TF activity is of considerable therapeutic interest but very few TFs have been successfully drugged. TF D...

TF-MAPS: fast high-resolution functional and allosteric mapping of DNA-binding proteins by @XianghuaLi2

Are Transcription Factors really 'undruggable'?

www.biorxiv.org/content/10.1...

Latest pre-print from our lab is out. Great work by @alexbendel.bsky.social and team.

Full deep mutational scan of an entire human protein interaction domain family

2M quantitative measurement of protein-protein interaction -> deep learning model to predict PPI from sequence

More details 👇

Under which circumstances do genomic neural networks learn motifs and their interactions? The use of neural networks to model genomic data in sequence-to-function scenarios has soared over the last decade. There remains much debate about whether these models are interpretable, either inher...

Under which circumstances do genomic neural networks learn motifs and their interactions?https://www.biorxiv.org/content/10.1101/2025.07.25.666754v1

Allosteric and Energetic Remodeling by Protein Domain Extensions Many functions of proteins are performed by independently folding structural units called domains. The structures of domains are conserved during evolution but they are not identical. For example, the...

New preprint from the allostery team
www.biorxiv.org/content/10.1...

🎲 Our paper on the genetics, energetics, and allostery in proteins with randomized cores and surfaces is out today @science.org!
🧬 By charting a protein’s sequence universe, we could rationalize which versions were kept through evolution – and why many stable ones were not.

Allostery is a widespread cause of loss-of-function variant pathogenicity Allosteric communication between non-contacting sites in proteins plays a fundamental role in biological regulation and drug action. While allosteric gain-of-function variants are known drivers of onc...

New preprint: Allostery is a widespread cause of loss-of-function variant pathogenicity by the great
@xt117.bsky.social
biorxiv.org/content/10.1...

Wellcome Sanger Institute - Genomics Research Institute in Cambridge We are a world-leading genomics research institute in Cambridge. Our work helps improve human health and understand life on Earth

Only a few days left to apply to become a group leader in our Generative Biology programme at @sangerinstitute.bsky.social
www.sanger.ac.uk

Arriving at the airport to fly to an AI conference and this happens #AIxBio25

The evolution of allostery in a protein family.
Aina's new preprint containing seven complete comparative allosteric maps biorxiv.org/content/10.1...

Massively parallel genetic perturbation suggests the energetic structure of an amyloid-β transition state The aggregation rates of >140,000 mutants reveal the energetic structure of an amyloid-β nucleation reaction transition state.

Alzheimer’s disease 🧠starts with a molecular domino effect - but what triggers the first piece to fall?
In our new study we cracked open the black box of early protein aggregation, and the findings could reshape how we fight neurodegeneration. 🧵👇

www.science.org/doi/10.1126/...

The genetic architecture of an allosteric hormone receptor Many proteins function as switches, detecting chemicals and transducing their concentrations into cellular responses. Receptor switches are key to the integration of environmental signals, yet it is n...

1 plant hormone receptor ☘️
3,500 mutants, to single-site saturation 🧬
>45,000 binding and abundance measurements 📶

Very happy to present our latest work – where deep mutational scanning meets the world of small molecules.



www.biorxiv.org/content/10.1...



With @benlehner.bsky.social

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The genetic architecture of an allosteric hormone receptor Many proteins function as switches, detecting chemicals and transducing their concentrations into cellular responses. Receptor switches are key to the integration of environmental signals, yet it is n...

Shoutout to the Maxi @maxstammnitz.bsky.social for pioneering dose-response methods and check out his pre-print too: www.biorxiv.org/content/10.1...

The genetic architecture of G-protein coupled receptor signaling G-protein coupled receptors (GPCRs) are the most abundant class of human receptors and drug targets. The vast majority of GPCR drugs bind the conserved orthosteric pocket, which can lead to non-specif...

GPCR-MAPS is now live! www.biorxiv.org/content/10.1...
A new platform for high resolution functional mapping of GPCRs with massive mutagenesis. We identify the core activation network, residues involved in biased signaling, and generate >7,000 full dose response curves. With @benlehner.bsky.social

Want to improve your protein or genomic language model’s performance at zero-shot variant effect prediction? We propose a simple adjustment to likelihood-based predicton

Our "Atlas of Variant Effects 2030 Roadmap" is live: zenodo.org/records/1542...

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Countdown officially started! #VariantEffect25 @varianteffect.bsky.social

Come and join us! We’re hiring a new Group Leader in Generative Biology at the @sangerinstitute.bsky.social

Building AI models or the data to train them?

Core funding of >$130M a year for a faculty of ~30.

www.nature.com/naturecareer...

acrobat.adobe.com/id/urn:aaid:...

pls RT!

Massive experimental quantification allows interpretable deep learning of protein aggregation xAI trained on >100,000 random peptides predicts and elucidates primary sequence determinants of aggregation.

We quantify the aggregation of >100,000 random protein sequences to train CANYA, a convolution-attention hybrid neural network to predict aggregation from sequence. With @bennibolo.bsky.social www.science.org/doi/10.1126/...

Deadline for abstract submissions and early bird reg for #VariantEffects25 is 1 March 2025.

Organised by @bennibolo.bsky.social @jonnyfrazer.bsky.social @benlehner.bsky.social @muffley.bsky.social @muffley.bsky.social and Mafalda Dias.

More info: events.ibecbarcelona.eu/mutational-s...

Quantifying metabolites using structure-switching aptamers coupled to DNA sequencing Nature Biotechnology - Metabolites can be quantified using a combination of aptamers and DNA barcodes.

Delighted to share our latest paper describing a method to read the levels of hundreds of metabolites or drugs in parallel using DNA sequencing. This method, which we call ‘smol-seq’ (Small MOLecule sequencing), harnesses the power of DNA sequencing for metabolite detection:
rdcu.be/d8xLv (1/6)

3 great computational positions available at @alloxbio.bsky.social to work with the great @ajfaure.bsky.social @juliadiumenge.bsky.social and team

At ALLOX @alloxbio.bsky.social in Barcelona we now have 3 computational positions available!

📌Structural Bioinformatics Scientist 👉 tinyurl.com/3rs46j4t
📌Platform Bioinformatician 👉 tinyurl.com/nyvazbke
📌Computational Chemist 👉 tinyurl.com/5n6vpem3

Apply or repost to help us spread the word 🙏

I am incredibly excited to announce that our project with @benlehner.bsky.social, @thomaswilhelm-blue.bsky.social, and the @crg.eu #TBDO has been awarded an ERC Proof of Concept Grant from @ercresearch.bsky.social! Huge thanks to everyone involved for their ongoing support – let's boost the science!

If you’d like to work on such projects, our team is hiring postdocs! We are part of the new Generative and Synthetic Genomics programme with @benlehner.bsky.social and Jussi Taipale, combining data generation at scale with AI to solve biology.Check out sanger.wd103.myworkdayjobs.com/en-US/Wellco...

Randomizing the human genome by engineering recombination between repeat elements We lack tools to edit DNA sequences at scales necessary to study 99% of the human genome that is noncoding. To address this gap, we applied CRISPR prime editing to insert recombination handles into re...

We're delighted to share our work on scrambling the human genome using prime editing, repetitive elements, and recombinases in @science.org , led by @jonaskoeppel.bsky.social , @f-raphael.bsky.social , with @proftomellis.bsky.social and George Church.
www.science.org/doi/10.1126/...

Nice highlighting of @taylor-mighell.bsky.social's GPCR pharmacochaperone preprint by @dereklowe.bsky.social @science.org www.biorxiv.org/content/10.1...

Enhancer scrambling strategy

We are happy to share our enhancer scramble story, a strategy to create hundreds of stochastic deletions, inversions, and duplications within mammalian gene regulatory regions and associate these new architectures with gene expression levels 🧵
www.biorxiv.org/content/10.1...

@crg.eu (winter) commute

The first ‘human domainome’ reveals the cause of a multitude of diseases An ingenious large-scale experiment in Barcelona has led to the creation of a catalog detailing the effects of half a million DNA mutations

Missense mutations are responsible for many heritable genetic disorders. Researchers led by @benlehner.bsky.social are carrying out large-scale experiments to understand why. Unstable proteins are emerging as a clear mechanism of action. Today in @elpais.com by @manuelansede.bsky.social.

Introducing Human Domainome v1, the largest and most comprehensive library of human protein variants to date, which maps the effects of +500K mutations across 522 domains. The study by @benlehner.bsky.social and Toni Beltran is out now in @nature.com. Illustration by @queralttolosa.bsky.social.