Connecting variants to functions

A genome-wide atlas of cell morphology reveals gene functions

adicorat — Mon, 27 Jan 2025 10:00:00 +0000

A genome-wide atlas of cell morphology reveals gene functions

By Allessandra DiCorato January 27, 2025

A genome-wide atlas of cell morphology reveals gene functions

PERISCOPE, a technique for genome-wide imaging screens, is helping ӳ��ý scientists understand the connections between genes and traits.

By Allessandra DiCorato

January 27, 2025

Credit: Maria Lozada, Neal Lab

Human cells imaged using Cell Painting. Cell nuclei are shown in blue, actin filaments in yellow, the endoplasmic reticulum in magenta, golgi bodies in cyan, and mitochondria in green.

Visualizing cells after editing specific genes can help scientists learn new details about the function of those genes. But using microscopy to do this at scale can be challenging, particularly when studying thousands of genes at a time.

Now, researchers at the ӳ��ý of MIT and Harvard, along with collaborators at Calico Life Sciences, have developed an approach that brings the power of microscopy imaging to genome-scale CRISPR screens in a scalable way.

PERISCOPE — which stands for perturbation effect readout in situ via single-cell optical phenotyping — combines two technologies developed by ӳ��ý scientists: Cell Painting, which can capture images and key measures of subcellular compartments at scale, and Optical Pooled Screening, which “barcodes” cells and uses CRISPR to systematically turn off individual genes to study their function in those cells.

The new technique lets scientists study the effects of perturbing over 20,000 genes on hundreds of image-based cellular features. Generating data with the method is more than 10 times less expensive than comparable high-dimensional approaches such as high-throughput single-cell RNA sequencing and can be adapted to study a wide variety of cell types. In Nature Methods, the researchers applied PERISCOPE to execute three whole-genome CRISPR screens to create an open-source atlas of cell morphology.

The study is the result of a collaboration between the labs of ӳ��ý co-senior authors JT Neal, institute scientist and co-director of type 2 diabetes systems genomics; Anne Carpenter, institute scientist and senior director of the Imaging Platform; and Paul Blainey, core institute member; as well as Calico, led by co-senior author Calvin Jan. ӳ��ý staff scientists Meraj Ramezani and Erin Weisbart, research associate Julia Bauman, and postdoctoral researcher Avtar Singh were all co-first authors on the study.

“This atlas itself is a first-in-class genome-scale resource for linking cell morphology to gene function, and I think it has a lot of discovery potential,” said Neal. “But maybe more importantly, all of the data is open access, and we’ve built really robust industrial-grade analysis pipelines that can be repurposed by anybody to analyze optical pooled screening data at scale.”

Morphological insights

First developed by Carpenter in 2013, Cell Painting is an assay designed to image multiple cell organelles at the same time and at scale, “painting” them different colors such as nuclei blue and mitochondria red. Machine-learning models then detect hundreds of subtle changes in the images, such as the texture of the cytoplasm or area of the nucleus, allowing researchers to test the effects of a gene perturbation, for example, on the cell.

When Neal joined the ӳ��ý in 2017 as a researcher in the Cancer Program, he was intrigued by the possibility of applying Cell Painting to cancer cells to learn the function of key genes and variants, which could help in the development of targeted therapies. He struck up a conversation with Carpenter, and also with Blainey, whose lab had developed optical pooled screening. The three started discussing how they might combine the two techniques and, in 2019, started building PERISCOPE, including an associated computational pipeline that integrates with Cell Profiler, in collaboration with Calico.

Complementary in situ sequencing image corresponding to the cell feature image shown above. Cell nuclei are labeled in blue; each smaller colored dot corresponds to a barcode labeling a cell in which a particular gene is turned off.

Credit: Maria Lozada, Neal Lab

In PERISCOPE, researchers introduce a library of guide RNAs targeting about 20,000 genes into cells. Next, they induce the expression of the DNA-cutting Cas9 enzyme to disable the genes targeted by the guides. They then convert the guide RNAs to complementary DNA, creating “barcodes” of the gene knocked out in each cell, which allow scientists to identify which gene has been turned off in each cell. This barcoding also enables the study of many genes in a single batch of cells, which is more efficient than testing them one by one. Finally, they use a standard widefield microscope to record images of the five Cell Painting stains and the four-color barcodes in the cells, followed by automated image analysis to extract cell features and link them to guide RNAs.

Using PERISCOPE, the researchers created atlases of the effects of knocking out genes in human lung and cervical cancer cells in standard cell culture media as well as in media that more closely resembles the physiological environment.

These atlases not only illustrated known biology but also revealed new information about poorly characterized genes. For example, they uncovered the function of TMEM251, a gene that has been linked to a rare genetic lysosomal storage disease. The team found that it is required for trafficking enzymes to lysosomes.

Next, the team is working on building the capacity to image even more colors simultaneously, expanding the range of traits that PERISCOPE can capture. They’re also collaborating with researchers in ӳ��ý’s Novo Nordisk Foundation Center for Genomic Mechanisms of Disease to create perturbation atlases in cardiometabolic cell types, and with ӳ��ý’s Ladders to Cures Accelerator to identify treatments for rare genetic disorders. Moreover, the team anticipates that PERISCOPE will be applicable to neurodegenerative disorders, such as Parkinson’s disease. Neal says PERISCOPE could one day even enable studies of the interactions between multiple genes.

“In the past, that’s been tricky because the genetic interaction space scales very quickly,” he said. “With PERISCOPE and other scalable optical pooled screening approaches, it’s now no longer far-fetched to envision very large genetic interaction screens.”

Funding

This work was supported by Calico Life Sciences LLC, the Novo Nordisk Foundation, and the National Institutes of Health.

Paper cited

Ramezani M, Bauman J, Singh A, Weisbart E, et al. A genome-wide atlas of cell morphology. Nature Methods. Online January 27, 2025. DOI: 10.1038/s41592-024-02537-7.

Tags:

Connecting variants to functions

Image-Based Profiling

New image-based cellular profiling tool peers deeply into metabolic biology

makenziekohler — Fri, 30 Jun 2023 14:30:09 +0000

A genome-wide atlas of cell morphology reveals gene functions

By Allessandra DiCorato January 27, 2025

A genome-wide atlas of cell morphology reveals gene functions

PERISCOPE, a technique for genome-wide imaging screens, is helping ӳ��ý scientists understand the connections between genes and traits.

By Allessandra DiCorato

January 27, 2025

Credit: Maria Lozada, Neal Lab

Human cells imaged using Cell Painting. Cell nuclei are shown in blue, actin filaments in yellow, the endoplasmic reticulum in magenta, golgi bodies in cyan, and mitochondria in green.

Morphological insights

Credit: Maria Lozada, Neal Lab

Funding

This work was supported by Calico Life Sciences LLC, the Novo Nordisk Foundation, and the National Institutes of Health.

Paper cited

Ramezani M, Bauman J, Singh A, Weisbart E, et al. A genome-wide atlas of cell morphology. Nature Methods. Online January 27, 2025. DOI: 10.1038/s41592-024-02537-7.

Tags:

Connecting variants to functions

Image-Based Profiling

Study finds how a genetic variant raises diabetes risk through an unexpected mechanism

tulrich@broadinstitute.org — Thu, 25 May 2023 15:01:46 +0000

A genome-wide atlas of cell morphology reveals gene functions

By Allessandra DiCorato January 27, 2025

A genome-wide atlas of cell morphology reveals gene functions

PERISCOPE, a technique for genome-wide imaging screens, is helping ӳ��ý scientists understand the connections between genes and traits.

By Allessandra DiCorato

January 27, 2025

Credit: Maria Lozada, Neal Lab

Human cells imaged using Cell Painting. Cell nuclei are shown in blue, actin filaments in yellow, the endoplasmic reticulum in magenta, golgi bodies in cyan, and mitochondria in green.

Morphological insights

Credit: Maria Lozada, Neal Lab

Funding

This work was supported by Calico Life Sciences LLC, the Novo Nordisk Foundation, and the National Institutes of Health.

Paper cited

Ramezani M, Bauman J, Singh A, Weisbart E, et al. A genome-wide atlas of cell morphology. Nature Methods. Online January 27, 2025. DOI: 10.1038/s41592-024-02537-7.

Tags:

Connecting variants to functions

Image-Based Profiling

Researchers use base editing to probe blood cell biology

Corie Lok — Tue, 02 May 2023 15:00:07 +0000

A genome-wide atlas of cell morphology reveals gene functions

By Allessandra DiCorato January 27, 2025

A genome-wide atlas of cell morphology reveals gene functions

PERISCOPE, a technique for genome-wide imaging screens, is helping ӳ��ý scientists understand the connections between genes and traits.

By Allessandra DiCorato

January 27, 2025

Credit: Maria Lozada, Neal Lab

Human cells imaged using Cell Painting. Cell nuclei are shown in blue, actin filaments in yellow, the endoplasmic reticulum in magenta, golgi bodies in cyan, and mitochondria in green.

Morphological insights

Credit: Maria Lozada, Neal Lab

Funding

This work was supported by Calico Life Sciences LLC, the Novo Nordisk Foundation, and the National Institutes of Health.

Paper cited

Ramezani M, Bauman J, Singh A, Weisbart E, et al. A genome-wide atlas of cell morphology. Nature Methods. Online January 27, 2025. DOI: 10.1038/s41592-024-02537-7.

Tags:

Connecting variants to functions

Image-Based Profiling

ӳ��ý Discovery Center in Cambridge opens to the public this October

kzusi@broadinstitute.org — Mon, 19 Sep 2022 14:53:09 +0000

A genome-wide atlas of cell morphology reveals gene functions

By Allessandra DiCorato January 27, 2025

A genome-wide atlas of cell morphology reveals gene functions

PERISCOPE, a technique for genome-wide imaging screens, is helping ӳ��ý scientists understand the connections between genes and traits.

By Allessandra DiCorato

January 27, 2025

Credit: Maria Lozada, Neal Lab

Human cells imaged using Cell Painting. Cell nuclei are shown in blue, actin filaments in yellow, the endoplasmic reticulum in magenta, golgi bodies in cyan, and mitochondria in green.

Morphological insights

Credit: Maria Lozada, Neal Lab

Funding

This work was supported by Calico Life Sciences LLC, the Novo Nordisk Foundation, and the National Institutes of Health.

Paper cited

Ramezani M, Bauman J, Singh A, Weisbart E, et al. A genome-wide atlas of cell morphology. Nature Methods. Online January 27, 2025. DOI: 10.1038/s41592-024-02537-7.

Tags:

Connecting variants to functions

Image-Based Profiling

Exploring autoimmunity's regulatory roots

tulrich@broadinstitute.org — Fri, 06 May 2022 13:30:21 +0000

A genome-wide atlas of cell morphology reveals gene functions

By Allessandra DiCorato January 27, 2025

A genome-wide atlas of cell morphology reveals gene functions

PERISCOPE, a technique for genome-wide imaging screens, is helping ӳ��ý scientists understand the connections between genes and traits.

By Allessandra DiCorato

January 27, 2025

Credit: Maria Lozada, Neal Lab

Human cells imaged using Cell Painting. Cell nuclei are shown in blue, actin filaments in yellow, the endoplasmic reticulum in magenta, golgi bodies in cyan, and mitochondria in green.

Morphological insights

Credit: Maria Lozada, Neal Lab

Funding

This work was supported by Calico Life Sciences LLC, the Novo Nordisk Foundation, and the National Institutes of Health.

Paper cited

Ramezani M, Bauman J, Singh A, Weisbart E, et al. A genome-wide atlas of cell morphology. Nature Methods. Online January 27, 2025. DOI: 10.1038/s41592-024-02537-7.

Tags:

Connecting variants to functions

Image-Based Profiling

Three autism risk genes have similar effects on brain development, but by different routes

tulrich@broadinstitute.org — Wed, 02 Feb 2022 16:32:08 +0000

A genome-wide atlas of cell morphology reveals gene functions

By Allessandra DiCorato January 27, 2025

A genome-wide atlas of cell morphology reveals gene functions

PERISCOPE, a technique for genome-wide imaging screens, is helping ӳ��ý scientists understand the connections between genes and traits.

By Allessandra DiCorato

January 27, 2025

Credit: Maria Lozada, Neal Lab

Human cells imaged using Cell Painting. Cell nuclei are shown in blue, actin filaments in yellow, the endoplasmic reticulum in magenta, golgi bodies in cyan, and mitochondria in green.

Morphological insights

Credit: Maria Lozada, Neal Lab

Funding

This work was supported by Calico Life Sciences LLC, the Novo Nordisk Foundation, and the National Institutes of Health.

Paper cited

Ramezani M, Bauman J, Singh A, Weisbart E, et al. A genome-wide atlas of cell morphology. Nature Methods. Online January 27, 2025. DOI: 10.1038/s41592-024-02537-7.

Tags:

Connecting variants to functions

Image-Based Profiling

New high-throughput method greatly expands view of how mutations impact cells

tulrich@broadinstitute.org — Thu, 20 Jan 2022 16:02:55 +0000

A genome-wide atlas of cell morphology reveals gene functions

By Allessandra DiCorato January 27, 2025

A genome-wide atlas of cell morphology reveals gene functions

PERISCOPE, a technique for genome-wide imaging screens, is helping ӳ��ý scientists understand the connections between genes and traits.

By Allessandra DiCorato

January 27, 2025

Credit: Maria Lozada, Neal Lab

Human cells imaged using Cell Painting. Cell nuclei are shown in blue, actin filaments in yellow, the endoplasmic reticulum in magenta, golgi bodies in cyan, and mitochondria in green.

Morphological insights

Credit: Maria Lozada, Neal Lab

Funding

This work was supported by Calico Life Sciences LLC, the Novo Nordisk Foundation, and the National Institutes of Health.

Paper cited

Ramezani M, Bauman J, Singh A, Weisbart E, et al. A genome-wide atlas of cell morphology. Nature Methods. Online January 27, 2025. DOI: 10.1038/s41592-024-02537-7.

Tags:

Connecting variants to functions

Image-Based Profiling

New maps link thousands of genetic variants to disease genes

Corie Lok — Wed, 07 Apr 2021 13:12:35 +0000

A genome-wide atlas of cell morphology reveals gene functions

By Allessandra DiCorato January 27, 2025

A genome-wide atlas of cell morphology reveals gene functions

PERISCOPE, a technique for genome-wide imaging screens, is helping ӳ��ý scientists understand the connections between genes and traits.

By Allessandra DiCorato

January 27, 2025

Credit: Maria Lozada, Neal Lab

Human cells imaged using Cell Painting. Cell nuclei are shown in blue, actin filaments in yellow, the endoplasmic reticulum in magenta, golgi bodies in cyan, and mitochondria in green.

Morphological insights

Credit: Maria Lozada, Neal Lab

Funding

This work was supported by Calico Life Sciences LLC, the Novo Nordisk Foundation, and the National Institutes of Health.

Paper cited

Ramezani M, Bauman J, Singh A, Weisbart E, et al. A genome-wide atlas of cell morphology. Nature Methods. Online January 27, 2025. DOI: 10.1038/s41592-024-02537-7.

Tags:

Connecting variants to functions

Image-Based Profiling

Large-scale tool helps reveal function of autism spectrum disorder genes

tulrich@broadinstitute.org — Thu, 03 Dec 2020 18:09:52 +0000

A genome-wide atlas of cell morphology reveals gene functions

By Allessandra DiCorato January 27, 2025

A genome-wide atlas of cell morphology reveals gene functions

PERISCOPE, a technique for genome-wide imaging screens, is helping ӳ��ý scientists understand the connections between genes and traits.

By Allessandra DiCorato

January 27, 2025

Credit: Maria Lozada, Neal Lab

Human cells imaged using Cell Painting. Cell nuclei are shown in blue, actin filaments in yellow, the endoplasmic reticulum in magenta, golgi bodies in cyan, and mitochondria in green.

Morphological insights

Credit: Maria Lozada, Neal Lab

Funding

This work was supported by Calico Life Sciences LLC, the Novo Nordisk Foundation, and the National Institutes of Health.

Paper cited

Ramezani M, Bauman J, Singh A, Weisbart E, et al. A genome-wide atlas of cell morphology. Nature Methods. Online January 27, 2025. DOI: 10.1038/s41592-024-02537-7.

Tags:

Connecting variants to functions

Image-Based Profiling

Connecting variants to functions

A genome-wide atlas of cell morphology reveals gene functions

A genome-wide atlas of cell morphology reveals gene functions

A genome-wide atlas of cell morphology reveals gene functions

Morphological insights

New image-based cellular profiling tool peers deeply into metabolic biology

A genome-wide atlas of cell morphology reveals gene functions

A genome-wide atlas of cell morphology reveals gene functions

Morphological insights

Study finds how a genetic variant raises diabetes risk through an unexpected mechanism

A genome-wide atlas of cell morphology reveals gene functions

A genome-wide atlas of cell morphology reveals gene functions

Morphological insights

Researchers use base editing to probe blood cell biology

A genome-wide atlas of cell morphology reveals gene functions

A genome-wide atlas of cell morphology reveals gene functions

Morphological insights

ӳ����ý Discovery Center in Cambridge opens to the public this October

A genome-wide atlas of cell morphology reveals gene functions

A genome-wide atlas of cell morphology reveals gene functions

Morphological insights

Exploring autoimmunity's regulatory roots

A genome-wide atlas of cell morphology reveals gene functions

A genome-wide atlas of cell morphology reveals gene functions

Morphological insights

Three autism risk genes have similar effects on brain development, but by different routes

A genome-wide atlas of cell morphology reveals gene functions

A genome-wide atlas of cell morphology reveals gene functions

Morphological insights

New high-throughput method greatly expands view of how mutations impact cells

A genome-wide atlas of cell morphology reveals gene functions

A genome-wide atlas of cell morphology reveals gene functions

Morphological insights

New maps link thousands of genetic variants to disease genes

A genome-wide atlas of cell morphology reveals gene functions

A genome-wide atlas of cell morphology reveals gene functions

Morphological insights

Large-scale tool helps reveal function of autism spectrum disorder genes

A genome-wide atlas of cell morphology reveals gene functions

A genome-wide atlas of cell morphology reveals gene functions

Morphological insights

ӳ��ý Discovery Center in Cambridge opens to the public this October