Thomas Norman
@normanlab.bsky.social
Associate Member in csBio at Memorial Sloan Kettering. Perturb-seq, single-cell functional genomics, and techniques for perturbing the genome.
Happy to answer questions if you're interested. More about the lab and our research here: thenormanlab.com
thenormanlab.com
February 4, 2026 at 3:22 PM
Happy to answer questions if you're interested. More about the lab and our research here: thenormanlab.com
We're also hiring a research technician. This is an opportunity to learn CRISPR screening and single-cell genomics directly from the people who developed these approaches. Previous techs have gone on to great biotech roles and graduate programs.
msk.wd108.myworkdayjobs.com/MSKCC_Career...
msk.wd108.myworkdayjobs.com/MSKCC_Career...
Research Technician, Norman Lab
About Us: The people of Memorial Sloan Kettering Cancer Center (MSK) are united by a singular mission: ending cancer for life. Our specialized care teams provide personalized, compassionate, expert ca...
msk.wd108.myworkdayjobs.com
February 4, 2026 at 3:22 PM
We're also hiring a research technician. This is an opportunity to learn CRISPR screening and single-cell genomics directly from the people who developed these approaches. Previous techs have gone on to great biotech roles and graduate programs.
msk.wd108.myworkdayjobs.com/MSKCC_Career...
msk.wd108.myworkdayjobs.com/MSKCC_Career...
We're looking for a postdoc with expertise in ECM biology, fibrosis, or mechanobiology who wants to apply functional genomics tools to their questions OR someone with a technology development background who wants to help build new methods.
msk.wd1.myworkdayjobs.com/MSKCC_Career...
msk.wd1.myworkdayjobs.com/MSKCC_Career...
msk.wd1.myworkdayjobs.com
February 4, 2026 at 3:22 PM
We're looking for a postdoc with expertise in ECM biology, fibrosis, or mechanobiology who wants to apply functional genomics tools to their questions OR someone with a technology development background who wants to help build new methods.
msk.wd1.myworkdayjobs.com/MSKCC_Career...
msk.wd1.myworkdayjobs.com/MSKCC_Career...
January 20, 2026 at 3:07 PM
These technologies open several future directions in large-scale genetics.
The lab is actively recruiting postdoctoral fellows and technicians. If you’re interested in working at the frontiers of experimental genomics, please get in touch!
The lab is actively recruiting postdoctoral fellows and technicians. If you’re interested in working at the frontiers of experimental genomics, please get in touch!
January 20, 2026 at 1:42 PM
These technologies open several future directions in large-scale genetics.
The lab is actively recruiting postdoctoral fellows and technicians. If you’re interested in working at the frontiers of experimental genomics, please get in touch!
The lab is actively recruiting postdoctoral fellows and technicians. If you’re interested in working at the frontiers of experimental genomics, please get in touch!
This project has been ongoing nearly since the start of my lab. Huge thanks to lead authors Anran (Angel) Tang and Rico Ardy for years of persistence, and to Rafaela Mendes for foundational early work during the height of COVID.
January 20, 2026 at 1:42 PM
This project has been ongoing nearly since the start of my lab. Huge thanks to lead authors Anran (Angel) Tang and Rico Ardy for years of persistence, and to Rafaela Mendes for foundational early work during the height of COVID.
One key implication: we think comprehensive genetic interaction mapping among all human genes may be within reach. Scaling to ~10,000 expressed genes would require ~2.5 billion lineages—about 100× beyond what we show here.
January 20, 2026 at 1:42 PM
One key implication: we think comprehensive genetic interaction mapping among all human genes may be within reach. Scaling to ~10,000 expressed genes would require ~2.5 billion lineages—about 100× beyond what we show here.
Why AP-1? Our results show that it responds to diverse biological processes. So AP-1 activity provides a readout with fitness-like breadth without requiring large changes in cell growth or death, enabling interaction mapping at much larger scale.
January 20, 2026 at 1:42 PM
Why AP-1? Our results show that it responds to diverse biological processes. So AP-1 activity provides a readout with fitness-like breadth without requiring large changes in cell growth or death, enabling interaction mapping at much larger scale.
Using PORTAL with an AP-1 reporter, we measured 665,856 pairwise perturbations across 612 genes and 46 million clonal lineages.
To our knowledge, this is the largest exhaustively measured GI map in human cells, and the first at this scale with a non-fitness phenotype.
To our knowledge, this is the largest exhaustively measured GI map in human cells, and the first at this scale with a non-fitness phenotype.
January 20, 2026 at 1:42 PM
Using PORTAL with an AP-1 reporter, we measured 665,856 pairwise perturbations across 612 genes and 46 million clonal lineages.
To our knowledge, this is the largest exhaustively measured GI map in human cells, and the first at this scale with a non-fitness phenotype.
To our knowledge, this is the largest exhaustively measured GI map in human cells, and the first at this scale with a non-fitness phenotype.
Finally, we developed a dual-sgRNA PORTAL vector using compact “mini” Pol III promoters. These pieces together enable systematic genetic interaction mapping, our main application.
(P.S. The same cassette can also be used for dual-sgRNA CROP-seq experiments.)
(P.S. The same cassette can also be used for dual-sgRNA CROP-seq experiments.)
January 20, 2026 at 1:42 PM
Finally, we developed a dual-sgRNA PORTAL vector using compact “mini” Pol III promoters. These pieces together enable systematic genetic interaction mapping, our main application.
(P.S. The same cassette can also be used for dual-sgRNA CROP-seq experiments.)
(P.S. The same cassette can also be used for dual-sgRNA CROP-seq experiments.)
Each clonal lineage thus becomes an independent replicate. (We show that single-cell resolution is also possible via combinatorial indexing.)
For example, here we see knockdown of KDM5C increasing AP-1 reporter activity across hundreds of lineages.
For example, here we see knockdown of KDM5C increasing AP-1 reporter activity across hundreds of lineages.
January 20, 2026 at 1:42 PM
Each clonal lineage thus becomes an independent replicate. (We show that single-cell resolution is also possible via combinatorial indexing.)
For example, here we see knockdown of KDM5C increasing AP-1 reporter activity across hundreds of lineages.
For example, here we see knockdown of KDM5C increasing AP-1 reporter activity across hundreds of lineages.
The PORTAL vector actually produces two transcripts:
• a pathway-responsive reporter
• a constitutive identity transcript for normalization
Both carry the sgRNA and a clonal barcode in their 3′ ends, linking phenotype to lineage.
• a pathway-responsive reporter
• a constitutive identity transcript for normalization
Both carry the sgRNA and a clonal barcode in their 3′ ends, linking phenotype to lineage.
January 20, 2026 at 1:42 PM
The PORTAL vector actually produces two transcripts:
• a pathway-responsive reporter
• a constitutive identity transcript for normalization
Both carry the sgRNA and a clonal barcode in their 3′ ends, linking phenotype to lineage.
• a pathway-responsive reporter
• a constitutive identity transcript for normalization
Both carry the sgRNA and a clonal barcode in their 3′ ends, linking phenotype to lineage.
To address the second bottleneck, we developed PORTAL (Perturbation Output via Reporter Transcriptional Activity in Lineages).
Instead of reading perturbation identity from genomic DNA, PORTAL encodes perturbation effects in expressed transcripts.
Instead of reading perturbation identity from genomic DNA, PORTAL encodes perturbation effects in expressed transcripts.
January 20, 2026 at 1:42 PM
To address the second bottleneck, we developed PORTAL (Perturbation Output via Reporter Transcriptional Activity in Lineages).
Instead of reading perturbation identity from genomic DNA, PORTAL encodes perturbation effects in expressed transcripts.
Instead of reading perturbation identity from genomic DNA, PORTAL encodes perturbation effects in expressed transcripts.
CAP cloning should be broadly useful wherever transformation is limiting, including lineage tracing, MPRAs, combinatorial protein or antibody engineering, toxic ORF libraries, synthetic biology circuits, and, as we show, new scales of functional genomic screens…
January 20, 2026 at 1:42 PM
CAP cloning should be broadly useful wherever transformation is limiting, including lineage tracing, MPRAs, combinatorial protein or antibody engineering, toxic ORF libraries, synthetic biology circuits, and, as we show, new scales of functional genomic screens…
The result is extremely even, high-complexity libraries.
For example, we cloned a library of 812 × 812 guide pairs × 120,000 clonal barcodes (~80 billion elements), recovering 99.99% of guide pairs with near-Gaussian representation.
For example, we cloned a library of 812 × 812 guide pairs × 120,000 clonal barcodes (~80 billion elements), recovering 99.99% of guide pairs with near-Gaussian representation.
January 20, 2026 at 1:42 PM
The result is extremely even, high-complexity libraries.
For example, we cloned a library of 812 × 812 guide pairs × 120,000 clonal barcodes (~80 billion elements), recovering 99.99% of guide pairs with near-Gaussian representation.
For example, we cloned a library of 812 × 812 guide pairs × 120,000 clonal barcodes (~80 billion elements), recovering 99.99% of guide pairs with near-Gaussian representation.
CAP cloning instead assembles and amplifies linear DNA in vitro, then uses TelN protelomerase to generate exonuclease-resistant, covalently closed molecules that package directly into lentivirus.
(Shoutout to Touchlight who pioneered this chemistry.)
(Shoutout to Touchlight who pioneered this chemistry.)
January 20, 2026 at 1:42 PM
CAP cloning instead assembles and amplifies linear DNA in vitro, then uses TelN protelomerase to generate exonuclease-resistant, covalently closed molecules that package directly into lentivirus.
(Shoutout to Touchlight who pioneered this chemistry.)
(Shoutout to Touchlight who pioneered this chemistry.)
In traditional cloning, you construct plasmids in vitro and then transform them into bacteria to amplify. That transformation step is where complexity dies, as anyone who has failed to clone a library has experienced firsthand.
January 20, 2026 at 1:42 PM
In traditional cloning, you construct plasmids in vitro and then transform them into bacteria to amplify. That transformation step is where complexity dies, as anyone who has failed to clone a library has experienced firsthand.
The first and likely most broadly useful advance is CAP cloning (Covalently closed Assembly Products), a new approach for cloning ultracomplex lentiviral libraries by avoiding bacterial transformation.
January 20, 2026 at 1:42 PM
The first and likely most broadly useful advance is CAP cloning (Covalently closed Assembly Products), a new approach for cloning ultracomplex lentiviral libraries by avoiding bacterial transformation.
Two bottlenecks limit scaling. First, even constructing very large perturbation libraries is hard. Second, most screens read out only a single molecule per cell—the sgRNA—which is an inefficient use of cells.
We address both with new technologies.
We address both with new technologies.
January 20, 2026 at 1:42 PM
Two bottlenecks limit scaling. First, even constructing very large perturbation libraries is hard. Second, most screens read out only a single molecule per cell—the sgRNA—which is an inefficient use of cells.
We address both with new technologies.
We address both with new technologies.
Genome-wide pooled CRISPR screens have been transformative tools. But many important problems lie beyond genome scale: mapping genetic interactions, interpreting variants, and perturbing regulatory elements all require far more perturbations than current methods support.
January 20, 2026 at 1:42 PM
Genome-wide pooled CRISPR screens have been transformative tools. But many important problems lie beyond genome scale: mapping genetic interactions, interpreting variants, and perturbing regulatory elements all require far more perturbations than current methods support.