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Stanford Spinoff’s Cell-Based Screening Tech Offers Bird’s-Eye View of Regulatory Systems

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Stanford University spinoff SwtichGear Genomics has developed new cell-based screening tools that use reporter technology to observe how different regulatory elements interact in living cells to influence gene expression in a particular pathway, according to company co-founder and CSO Nathan Trinklein.
 
The company, based in Menlo Park, Calif., uses Promega’s optimized luciferase reporter gene, and provides pathway screening products and services using its SwitchGear platform, Trinklein said.
 
One of its existing applications is to study pathways associated with hypoxia. Currently, researchers screening for molecules that affect hypoxia take the promoter for VEGF and use it as a reporter to determine if their small molecule affected the hypoxia pathway, Trinklein told CBA News this week.
 
By comparison, SwitchGear’s technology, which it calls functional macroarrays, enables researchers to characterize entire pathways rather than having to rely on a single reporter, Trinklein said. Research groups can measure all of the independent components of the pathway and get a comprehensive picture of it.
 
“Our business model is to enable research groups to screen entire pathways in a comprehensive way,” said Trinklein. “It’s taking reporter technology and scaling that to the entire genome, so you can get a complete picture of how these different regulatory elements interact in different conditions in living cells to regulate gene expression.”
 
Trinklein, who described SwtichGear’s technology at the World Pharmaceutical Congress in Philadelphia last week, said the company attaches different regulatory elements from the human genome to luciferase in a reporter plasmid.
 
The company has libraries containing thousands of unique regulatory elements from the human genome in a microplate format so that each element can be measured independently, Trinklein said.
 
He said that these elements, which include promoters of cancer-related genes, can be used to screen and functionally characterize transcription factor binding sites and miRNA targets, detail the mechanism of action of gene regulation, and screen compounds for their effect on the entire pathway.
 
SwitchGear calls these tools Functional Macroarrays, Trinklein said. Each macroarray is available in a 96- or 384-well format, where each well has a unique human promoter, 3’ UTR, or long-range element, which are sequence-verified and in a transfection-ready format.
 
Trinklein said that one of the company’s first products was a panel of about 400 promoters related to hypoxia genes. SwitchGear scientists did a proof-of-principle experiment showing how the tool could be used to measure hypoxia, which can occur during tumor growth or as a result of a stroke or myocardial infarction.
 
The proof-of-principle studies also showed how the panel can be used to measure that response when it is induced by a small molecule or some other chemical inducer of the hypoxia pathway, said Trinklein.
 
For instance, the company found that 341 of 394 promoters change significantly depending on the addition of certain compounds or the use of certain cell lines, including HT-1080, HCT-116, or SKNSH. Overall, 144 promoters were up-regulated and 197 were down-regulated.
 
SwitchGear also found that approximately 25 percent of these responsive promoters were new discoveries, and observed distinct patterns of activity between cell lines and compounds.  
 

“Our business model is to sell a new type of research tool that will allow people to screen entire genetic pathways.”

“What we have seen, and other groups have seen, is that different molecules that are similar to one another may affect a particular pathway in different ways,” Trinklein said. “So it is crucial to determine whether you are affecting part of the pathway, and not the entire pathway.”
 
Trinklein said that the hypoxia panel is part of SwitchGear’s overall oncology panel. The company also has an additional 3,000 promoters that are related to other aspects of oncology cell, including DNA damage, apoptosis, and p53, among others.
 
Gearing Up
 
Trinklein said that he and SwitchGear co-founder Shelley Force-Aldred managed a project in the lab of Richard Myers at Stanford for several years that was a part of the National Human Genome Research Institute’s ENCODE project.
 
In the course of managing that project, Trinklein and Force-Aldred, who is the company’s COO and president, developed these functional macroarray approaches. After their stint with ENCODE ended, they and Myers, chairman of the genetics department at Stanford, founded SwitchGear to commercialize those approaches.
 
The company has been fully operational for about 18 months, said Trinklein. He described its customers as “a blend” of academic research groups and biotech and pharma companies that “are now beginning to adopt these tools as a way of integrating them into the screening process.”
 
“I think a lot of our biggest growth opportunities are with different biotech and pharma companies that will be able to use these tools to further their cell-based screening approaches and obtain more valuable information as they prioritize their compounds,” said Trinklein.     
 
SwitchGear is soon going to release a tool to study different nuclear receptor pathways including the estrogen receptor, androgen receptor, glucocorticoid receptor, and peroxisome proliferator-activated receptor, Trinklein said.  

 

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