Ben Lehner
@benlehner.bsky.social
Solve Biology
Head of Generative Genomics, Wellcome Sanger Institute, Cambridge, UK
Systems + Synthetic Biology, CRG, Barcelona
http://barcelonacollaboratorium.com http://allox.bio https://www.sanger.ac.uk/programme/generative-and-synthetic-genomics/
Head of Generative Genomics, Wellcome Sanger Institute, Cambridge, UK
Systems + Synthetic Biology, CRG, Barcelona
http://barcelonacollaboratorium.com http://allox.bio https://www.sanger.ac.uk/programme/generative-and-synthetic-genomics/
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...
Are Transcription Factors really 'undruggable'?
www.biorxiv.org/content/10.1...
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...
www.biorxiv.org
October 23, 2025 at 12:50 PM
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...
Are Transcription Factors really 'undruggable'?
www.biorxiv.org/content/10.1...
Reposted by Ben Lehner
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 👇
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 👇
I am happy to finally share this preprint of my PhD project in @guillaumediss.bsky.social lab at the FMI in Basel.
We used ddPCA to map the genetic architecture of the entire human bZIP interaction network.
www.biorxiv.org/content/10.1...
Thanks to all our co-authors for the great collaboration!
We used ddPCA to map the genetic architecture of the entire human bZIP interaction network.
www.biorxiv.org/content/10.1...
Thanks to all our co-authors for the great collaboration!
The genetic architecture of the human bZIP family
Generative biology holds the promise to transform our ability to design and understand living systems by creating novel proteins, pathways, and organisms with tailored functions that address challenge...
www.biorxiv.org
August 25, 2025 at 3:37 PM
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 👇
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?https://www.biorxiv.org/content/10.1101/2025.07.25.666754v1
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...
www.biorxiv.org
August 1, 2025 at 6:18 AM
Under which circumstances do genomic neural networks learn motifs and their interactions?https://www.biorxiv.org/content/10.1101/2025.07.25.666754v1
New preprint from the allostery team
www.biorxiv.org/content/10.1...
www.biorxiv.org/content/10.1...
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...
www.biorxiv.org
July 31, 2025 at 4:21 PM
New preprint from the allostery team
www.biorxiv.org/content/10.1...
www.biorxiv.org/content/10.1...
Reposted by Ben Lehner
🎲 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.
🧬 By charting a protein’s sequence universe, we could rationalize which versions were kept through evolution – and why many stable ones were not.
July 25, 2025 at 6:27 AM
🎲 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.
🧬 By charting a protein’s sequence universe, we could rationalize which versions were kept through evolution – and why many stable ones were not.
New preprint: Allostery is a widespread cause of loss-of-function variant pathogenicity by the great
@xt117.bsky.social
biorxiv.org/content/10.1...
@xt117.bsky.social
biorxiv.org/content/10.1...
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...
biorxiv.org
June 25, 2025 at 6:11 PM
New preprint: Allostery is a widespread cause of loss-of-function variant pathogenicity by the great
@xt117.bsky.social
biorxiv.org/content/10.1...
@xt117.bsky.social
biorxiv.org/content/10.1...
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
www.sanger.ac.uk
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
www.sanger.ac.uk
June 25, 2025 at 3:30 PM
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
www.sanger.ac.uk
The evolution of allostery in a protein family.
Aina's new preprint containing seven complete comparative allosteric maps biorxiv.org/content/10.1...
Aina's new preprint containing seven complete comparative allosteric maps biorxiv.org/content/10.1...
biorxiv.org
June 21, 2025 at 3:38 PM
The evolution of allostery in a protein family.
Aina's new preprint containing seven complete comparative allosteric maps biorxiv.org/content/10.1...
Aina's new preprint containing seven complete comparative allosteric maps biorxiv.org/content/10.1...
Reposted by Ben Lehner
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/...
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/...
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.
www.science.org
June 12, 2025 at 12:54 PM
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/...
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/...
Reposted by Ben Lehner
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
[1/7]
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
[1/7]
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...
www.biorxiv.org
June 2, 2025 at 1:36 PM
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
[1/7]
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
[1/7]
Reposted by Ben Lehner
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 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...
www.biorxiv.org
June 1, 2025 at 7:48 AM
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...
Reposted by Ben Lehner
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
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
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...
www.biorxiv.org
June 1, 2025 at 7:48 AM
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
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
Reposted by Ben Lehner
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
New preprint in collaboration with @paulinanunezv.bsky.social supervised by @jonnyfrazer.bsky.social and Mafalda Dias – we propose a simple approach to improving zero-shot variant effect prediction in pre-existing protein and genome language models: 🧶 1/n
www.biorxiv.org/content/10.1...
www.biorxiv.org/content/10.1...
From Likelihood to Fitness: Improving Variant Effect Prediction in Protein and Genome Language Models
Generative models trained on natural sequences are increasingly used to predict the effects of genetic variation, enabling progress in therapeutic design, disease risk prediction, and synthetic biolog...
www.biorxiv.org
May 26, 2025 at 5:33 PM
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
Reposted by Ben Lehner
Reposted by Ben Lehner
Countdown officially started! #VariantEffect25 @varianteffect.bsky.social
Very nice blogpost from @pascalnotin.bsky.social. You can catch him in Barcelona at www.varianteffect.org/mss2025/ #VariantEffect25 in a couple of weeks if you want to chat! Also, watch this space -- hoping to continue this discussion soon!
May 9, 2025 at 2:37 PM
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!
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!
May 6, 2025 at 2:59 PM
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!
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!
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/...
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.
www.science.org
May 4, 2025 at 10:40 AM
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/...
Reposted by Ben Lehner
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...
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...
We're excited to host the 8th annual meeting of the ‘Mutational Scanning Symposium’ in Barcelona. Experts from around will present their work, discuss new methods and provide insights on the burgeoning discipline. 21-23 May, with onsite & virtual options. #VariantEffect25
February 24, 2025 at 5:12 PM
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...
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...
Reposted by Ben Lehner
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)
rdcu.be/d8xLv (1/6)
Quantifying metabolites using structure-switching aptamers coupled to DNA sequencing
Nature Biotechnology - Metabolites can be quantified using a combination of aptamers and DNA barcodes.
rdcu.be
February 4, 2025 at 1:54 PM
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)
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 🙏
📌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 🙏
February 3, 2025 at 12:01 PM
3 great computational positions available at @alloxbio.bsky.social to work with the great @ajfaure.bsky.social @juliadiumenge.bsky.social and team
Reposted by Ben Lehner
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 🙏
📌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 🙏
January 30, 2025 at 2:43 PM
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 🙏
📌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 🙏
Reposted by Ben Lehner
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!
Congratulations to @benlehner.bsky.social @albertescobedo.bsky.social and @thomaswilhelm-blue.bsky.social for receiving an ERC Proof of Concept Grant!
The CRG researchers are among a select group of 134 scientists across Europe who will explore the commercial potential of their research. #ERCPoC
The CRG researchers are among a select group of 134 scientists across Europe who will explore the commercial potential of their research. #ERCPoC
134 researchers supported to turn their science into practice
In the final round of the 2024 European Research Council (ERC) Proof of Concept grant competition, 134 projects will receive support, bringing the total number of grants awarded under the 2024 work pr...
erc.europa.eu
January 23, 2025 at 2:07 PM
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!
Reposted by Ben Lehner
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...
Postdoctoral Fellow | Generative and Synthetic Genomics
Do you want to help us improve human health and understand life on Earth? Make your mark by shaping the future to enable or deliver life-changing science to solve some of humanity’s greatest challenge...
sanger.wd103.myworkdayjobs.com
January 31, 2025 at 1:49 PM
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...
Reposted by Ben Lehner
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/...
www.science.org/doi/10.1126/...
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...
www.science.org
January 31, 2025 at 1:49 PM
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/...
www.science.org/doi/10.1126/...