A new single-cell platform called PerturbFate can track how hundreds of genetic mutations affect cells and identify shared regulatory mechanisms, potentially enabling therapies that target common pathways rather than individual mutations in diseases like cancer and neurodegeneration.
A new study from researchers at Rockefeller University has presented a technology that could change the way scientists understand and treat complex diseases such as cancer and neurodegeneration.
Researchers have developed a platform called PerturbFate, designed to track how large numbers of disease-associated genetic mutations affect cells and where their effects converge. The approach provides a potential route to therapies that target shared mechanisms rather than individual mutations.
Diseases like cancer often occur from hundreds of genetic alterations across multiple biological pathways. While advances in genomics have made it easier to identify these mutations, translating that knowledge into treatments has proved far more difficult.
Tackling a growing challenge in biomedicine
According to the researchers, this growing list of disease-linked genes has created a bottleneck in drug development. Many mutations influence different cellular processes, making it challenging to design treatments that address them collectively.
According to the researchers, this growing list of disease-linked genes has created a bottleneck in drug development
“We focus here on cancer drug resistance, but the paper really starts from a broader question: once you know that a disease is associated with hundreds of genes, how do you design one therapy to target it?” said Junyue Cao, who led the study. “We wondered whether all these different genes may be mediated by some shared downstream signalling that we can discover and target instead.”
The concept centres on identifying ’regulatory nodes’ – shared control points within cells that govern how genetic changes ultimately influence behaviour.
Tracking genetic changes in real time
To achieve this, the team developed PerturbFate, a platform capable of analysing how hundreds to thousands of genetic disruptions affect individual cells over time.
Created by graduate researcher Zihan Xu, the system simultaneously tracks gene expression, RNA dynamics and chromatin accessibility within single cells. This allows scientists to observe how different mutations reshape cellular processes in real time.
“This technology lets us perturb hundreds to thousands of genes in parallel and then measure the detailed molecular changes in each individual cell,” Cao said. “That allows us to link many different genetic perturbations to their downstream effects and identify regulatory nodes.”
Insights into melanoma drug resistance
As a proof of concept, the researchers applied the platform to melanoma, focusing on resistance to the drug Vemurafenib.
The team disrupted 143 genes linked to drug resistance and analysed more than 300,000 individual cells. Despite the diversity of genetic changes, many of the mutations drove cells towards the same resistant state.
The team disrupted 143 genes linked to drug resistance and analysed more than 300,000 individual cells
“We’re capturing not just gene expression, but also RNA dynamics and chromatin state,” Cao said. “That’s critical for identifying the upstream regulators that drive these disease states.”
Further analysis revealed that even when mutations followed different biological routes, they often converged on the same survival signal, known as VEGFC. Blocking this signal significantly reduced drug resistance, highlighting a promising target for future therapies.
Toward broader applications
The findings suggest that complex diseases may not require equally complex treatments. Instead of targeting each mutation individually, researchers may be able to focus on shared regulatory mechanisms.
The study also uncovered an important nuance involving the Mediator complex, a key regulator of gene activity. Disrupting different components of this system triggered drug resistance through distinct pathways, yet still led to the same end point, reinforcing the idea of convergent biological processes.
Looking ahead, the team plans to expand the use of PerturbFate beyond cell cultures into living systems and apply it to other conditions, including ageing and Alzheimer’s disease.
“This is just a starting point,” Cao said. “Now that we’ve demonstrated the approach in a simple model, we’re working to extend it into living systems to study even more complex diseases.”
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